• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report

Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)

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Last updated: 3/14/2024
Years published: 1996, 1998, 2001, 2004, 2010, 2013, 2016, 2020, 2024


Acknowledgment

NORD gratefully acknowledges Jerry Vockley, MD, PhD, University of Pittsburgh, Chief of Medical Genetics, Children’s Hospital of Pittsburgh of UPMC, for assistance in the preparation of this report.


Disease Overview

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism that is inherited in an autosomal recessive pattern. It occurs when an enzyme needed to break down long-chain fatty acids is missing or not working properly. VLCADD is one of the metabolic diseases known as fatty acid oxidation (FOD) diseases. In the past, the name long-chain acyl-CoA dehydrogenase deficiency (LCADD) was applied to one such disease, but today it is clear that all cases once thought to be LCADD are actually VLCADD.

The breakdown of fatty acids takes place in the mitochondria found in each cell. The mitochondria are small, well-defined structures that are located in the cytoplasm of cells and in which energy is generated from the breakdown of complex substances into simpler ones.

Classically, two forms of VLCADD have been described: an early-onset, severe form which, if unrecognized and undiagnosed, can lead to extreme weakness of the heart muscles (cardiomyopathy) and be life-threatening, and a later-onset, milder form that is characterized by repeated bouts of low blood sugar (hypoglycemia). In reality, patients can present with a combination of symptoms and the disease is best thought of as being a continuum. Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, most VLCADD infants in the United States are being diagnosed in the neonatal period.

 

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Synonyms

  • ACADL
  • nonketotic hypoglycemia caused by deficiency of acyl-CoA dehydrogenase
  • VLCAD
  • long chain fatty acid oxidation disorder
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Signs & Symptoms

Children with early-onset VLCADD present with symptoms within days or weeks after birth. These infants show signs of low blood sugar (hypoglycemia) including irritability and listlessness (lethargy). Blood ammonia levels can be high. Infants also are at risk for weakness of the heart muscles (cardiomyopathy), abnormal heart rhythms, and cardiorespiratory failure. Similar symptoms can occur any time in the first few months to years of life. Cardiomyopathy is uncommon in infancy but can be life threatening when present. The incidence of hypoglycemia decreases with age and is uncommon after about age six. Thereafter, muscle symptoms predominate including periodic attacks of pain, fatigue and/or muscle breakdown (rhabdomyolysis) with activity or otherwise mild illnesses. Some patients can have their first symptoms in early adolescence. Cardiomyopathy and cardiac arrhythmias can occur at any age.

The hypoglycemia associated with VLCADD occurs with little or no accumulation of ketone bodies (hypoketotic hypoglycemia) in the blood. (Ketone bodies are chemical substances normally produced by fatty acid metabolism in the liver.) There are very complicated patterns of blood chemicals and concentrations of unusual acids in the blood. A patient’s blood or urine will be examined for these patterns if VLCADD is suspected. However, because hypoglycemia usually occurs well after other symptoms, home glucose monitoring is not typically useful.

Affected individuals of any age are at risk for recurrent increased acid levels in blood and body tissues (metabolic acidosis) and cardiac arrest due to cardiomyopathy or arrythmias. Without prompt, appropriate treatment, such acute episodes are life-threatening. (For further information, please see Standard Therapies below.)

Individuals with VLCADD deficiency can have fat deposits (fatty infiltration) and abnormal enlargement of the liver (hepatomegaly); poor muscle tone (hypotonia) and/or evidence of cardiomyopathy. For example, there can be abnormal thickening (hypertrophy) or stretching and enlargement (dilation) of the heart (i.e., hypertrophic or dilated cardiomyopathy). Cardiomyopathy can lead to weakening in the force of heart contractions, decreased efficiency in the circulation of blood through the lungs and to the rest of the body (heart failure) and various associated symptoms depending on the nature and severity of the condition, patient age and other factors.

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Causes

VLCADD is a genetic disorder of fatty acid metabolism. Metabolic disorders result from abnormal structure and functioning of a specific protein known as an enzyme. Enzymes are proteins that speed up the chemical reactions of the body. Enzymes are complicated proteins that must be folded in very precise ways to do their job of speeding up specific chemical reactions so that metabolism may proceed.

VLCADD deficiency is inherited in an autosomal recessive pattern. Original reports of long chain Acyl-CoA dehydrogenase deficiency (LCAD) in the medical literature were in error and all previously published cases of LCAD deficiency have been shown to be VLCAD deficiency.

Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

 

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Affected populations

VLCADD was originally described in 1992 and is now recognized as having an incidence of 1:40,000 babies. The introduction of heel-stick tandem mass spectrometry for the early diagnosis of VLCAD in newborns has markedly increased the number of infants diagnosed with VLCADD.

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Diagnosis

VLCADD is diagnosed based upon a thorough clinical evaluation, identification of characteristic findings (e.g., hypoketotic hypoglycemia, severe skeletal muscle weakness, heart enlargement), and the results of various specialized tests, including analysis conducted on various specimens, such as urine, blood, muscle, liver tissue, skin cells (cultured fibroblasts) and/or white blood cells (leukocytes). A thorough and complete family history is especially important to determine if there is an episode of sudden infant death (SID) in the family’s past. One estimate is that prior to the advent of newborn screening VLCAD deficiency was responsible for up to 5% of all SIDS deaths. VLCADD is included on the recommended uniform screening panel in the United States. DNA testing by gene sequencing is now the most common confirmatory test in a child suspected to have VLCADD.

In individuals with the disorder, urine organic acid analysis typically contains reduced or absent ketone bodies and elevated levels of certain dicarboxylic acids (i.e., dicarboxylic aciduria, e.g., increased C6-C10, C12-C14 dicarboxylic acids). In some patients, there may be increased blood levels of the enzyme creatine phosphokinase (CPK) and the abnormal presence of myoglobin in the urine (myoglobinuria).

Removal (biopsy) and microscopic evaluation of small samples of liver tissue often reveal fatty infiltration and structural changes of mitochondria during illness, though this is not necessary for clinical diagnosis. In addition, abnormal enlargement of the heart (cardiomegaly) associated with cardiomyopathy can be apparent upon chest x-ray examination or echocardiogram.

Prenatal diagnosis is available by enzyme measurement of either cultured cells or cells obtained from the amniotic fluid or during chorionic villus sampling (CVS); however, testing of cells by DNA sequencing is now the most used diagnostic method.

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Standard Therapies

Treatment
Disease management and treatment are primarily directed toward preventing and controlling acute episodes. Newborns should not fast more than 4 hours (including at night) for the first 6 months of age. This can be increased gradually to 8 hours over the next 6 months of age, then 8-12 hours after age three. Additional preventive measures include maintaining a low-fat, high-carbohydrate diet, with frequent feeding (i.e., to keep periods of fasting to a minimum). Additional recommendations include the use of low-fat nutritional supplements and medium-chain triglycerides (e.g., MCT oil).

Triheptanoin has been approved by the U.S. Food and Drug Administration (FDA) for treatment of long chain fatty acid oxidation disorders including VLCADD and improves long term clinical outcome compared to use of similar doses of MCT oil.

Supplementation with carnitine (Carnitor) is somewhat controversial and most metabolic physicians will wait until laboratory evidence of carnitine deficiency develops before prescribing it. Riboflavin, sometimes recommended in the past, does not seem to be beneficial.

If hospitalized for an acute episode, treatment requires the prompt administration of intravenous glucose (10% dextrose) and additional supportive measures as necessary.

Genetic counseling is recommended for families of all affected individuals. In addition, diagnostic testing of siblings is crucial to help detect and appropriately manage the condition. Other treatment for this disorder is symptomatic and supportive.

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Clinical Trials and Studies

Bezafibrate is an experimental medication originally developed to lower blood cholesterol. It has coincidentally been shown to increase the amount of VLCAD protein in cells. Limited clinical studies have been published to study the use of bezafibrate in VLCAD deficiency, but no active clinical trials are in progress.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

 

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References

TEXTBOOKS
Vockley J, Organic Acidemias and Disorders of Fatty Acid Oxidation. In: Emory and Rimoin Eds. Principles and Practice of Medical Genetics 5th edition. Harcourt Health Sciences Companies. 2006.

Eaton S. Very Long-Chain Acyl-CoA Dehydrogenase Deficiency. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:439-40.

Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, Pa: W.B. Saunders Company; 2000:377-80.

Roe CR, Ding J. Mitochondrial Fatty Acid Oxidation Disorders. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:2297-326.

Vockley J, Rinaldo P, Bennett MJ, et al. Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways. Mol Genet Metab. 2000;71:10-18.

JOURNAL ARTICLES
Schiff M, Mohsen AW, Karunanidhi A, McCracken E, Yeasted R, Vockley J. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013;109(1):21-7.

Shigematsu Y, Hirano S, Hata I, et al. Selective screening for fatty acid oxidation disorders by tandem mass spectrometry: difficulties in practical discrimination. J Chromatograph B Analyt Technol Biomed Life Sci. 2003;792:63-72.

Kluge S, Kuhnelt P, Block A, et al. A young woman with persistent hypoglycemia, rhabdomyolysis, and coma: recognizing fatty acid oxidation defects in adults. Crit Care Med. 2003;31:1273-76.

Spiekerkoetter U, Tenenbaum T, Heusch A, et al. Cardiomyopathy and Pericardial Effusion Point to a Fatty Acid b-Oxidation Defect after exclusion of an Underlying Infection. Pediatr Cardiol. 2003;24:295-97.

Solis JO, Singh RH. Management of fatty acid oxidation disorders: a survey of current treatment strategies. J Am Diet Assoc. 2002;102:1800-03.

Wilcox RL, Nelson CC, Stenzel P, et al. Postmortem screening for fatty acid oxidation disorders by analysis of Guthrie cards by tandem mass spectrometry in sudden unexpected death in infancy. J Pediatr. 2002;141:833-36.

Boles RG. Very long-chain acyl CoA dehydrogenase deficiency in an infant presenting with massive hepatomegaly. J Inherit Metab Dis. 2002;25:315-16.

Gregersen N, Andresen BS, Corydon MJ, et al. Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Hum Mutat. 2001;18:169-89.

Marsden D, Nyhan WL, Barshop BA. Creatine kinase and uric acid: early warning for metabolic imbalance resulting from disorders of fatty acid oxidation. Eur J Pediatr. 2001;160:599-602.

Wood JC, Magera MJ, Rinaldo P, et al. Diagnosis of very long-chain acyl-CoA dehydrogenase deficiency from an infant’s newborn screening card. Pediatrics. 2001;108:E19.

Touma EH, Rashed MS, Vianey-Saban C, et al. A severe genotype with favorable outcome in very long-chain acyl-CoA dehydrogenase deficiency . Arch Dis Child. 2001;84:58-60.

Zytkovicz TH, Fitzgerald EF, Marsden D, et al. Tandem mass spectroscopic analysis for amino, organic and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem. 2001;47:1945-55.

Gregersen N. Andresen BS, Bross P. Prevalent mutations in fatty acid oxidation disorders: diagnostic considerations. Eur J Pediatr. 2000;159 Suppl 3:S213-18.

Gregersen N, Bross P, Jorgensen MM, et al. Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders. J Inherit Metab Dis. 2000;23:441-47.

Roe CR, Wiltse HE, Sweetman L, et al. Death caused by perioperative fasting and sedation in a child with unrecognized very long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. 2000;136:397-99.

Scholte HR, Van Coster RN, de Jonge PC, et al. Myopathy in very long-chain acyl-CoA dehydrogenase deficiency: clinical and biochemical differences with fatal cardiac phenotype. Neuromuscul Disord. 1999;9:313-19.

INTERNET
Baby’s First Test: Very-Long-Chain Acyl-CoA DehydrogenaseDdeficiency. 2015. Available at: http://www.babysfirsttest.org/newborn-screening/conditions/very-long-chain-acyl-coa-dehydrogenase-deficiency Accessed Feb 28, 2024.

Vianey-Saban C. Acyl-CoA dehydrogenase, very long chain, deficiency of. Orphanet. Last update: February 2014. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=26793 Accessed Feb 28, 2024.

VLCAD Deficiency. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number: 201475; Last Update: 09/12/2022. Available at: http://www.omim.org/entry/201475?search=201475&highlight=201475 Accessed Feb 28, 2024.

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