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.
Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism that is transmitted as an autosomal recessive trait. It occurs when an enzyme needed to break down certain very 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 bodies that are found in the cytoplasm of cells and in which energy is generated from the breakdown of complex substances into simpler ones (mitochondrial oxidation).
Classically, two forms of VLCADD have been described: an early-onset, severe form which, if unrecognized and undiagnosed, may lead to extreme weakness of the heart muscles (cardiomyopathy) and may be life-threatening, and a later-onset, milder form that is characterized by repeated bouts of low blood sugar (hypoglycemia). In reality, patients may 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 detected neonatal period.
Children with early-onset VLCADD present with symptoms within days or weeks after birth. These infants also show signs of low blood sugar (hypoglycemia), irritability and listlessness (lethargy). From ages two or three months to about two years, infants with this form of the disorder will be at risk for thickening of the heart muscles (hypertrophic cardiomyopathy), abnormal heart rhythms and cardiorespiratory failure. Cardiomyopathy is rare in infancy, but may be life threatening when present.
Later-onset VLCADD may present with recurrent episodes of lethargy and even coma associated with low blood sugar during infancy and a noticeably enlarged liver (hepatomegaly) during childhood. During later childhood and early adulthood, the patient hypoglycemia becomes less common and patients instead experiences periodic attacks muscle pain and breakdown (rhabdomyolysis).
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 will be examined for these patterns if VLCADD is suspected.
Affected individuals may begin to experience recurrent increased acid levels in blood and body tissues (metabolic acidosis); sudden cessation of breathing (respiratory arrest) and even cardiac arrest. These symptoms may be associated with cardiomyopathy [see below]); listlessness, severe drowsiness (lethargy), and coma. Without prompt, appropriate treatment, such acute episodes may lead to potentially life-threatening complications. (For further information, please see Standard Therapies below.)
Individuals with VLCADD deficiency may have fat deposits (fatty infiltration) and abnormal enlargement of the liver (hepatomegaly); poor muscle tone (hypotonia); and/or evidence of cardiomyopathy. For example, there may be abnormal thickening (hypertrophy) or stretching and enlargement (dilation) of the left lower chamber (ventricle) of the heart (i.e., hypertrophic or dilated cardiomyopathy). Cardiomyopathy may 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 that may depend upon the nature and severity of the condition, patient age, and other factors.
VLCADD deficiency is inherited in an autosomal recessive fashion. The gene for VLCAD (ACADVL) is found at gene map locus 17p11.2-p11.1. Original reports of long chain Acyl-CoA dehydrogenase deficiency (LCAD) in the literature were in error and all previously published cases of LCAD deficiency have been shown to be VLCAD deficiency.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 17p11.2-p11.1” refers to a region between bands 11.2 and 11.1 on the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits one copy of a gene that does not function properly from each parent. If an individual receives one normal gene and one gene for the disease, 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 defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait 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.
As noted above, 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 in order to do their job of speeding up specific chemical reactions so that metabolism may proceed.
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 in which the disorder is detected.
VLCADD may be 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 in order 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.
In individuals with the disorder, urine organic acid analysis typically reveals 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 cases, 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 may also reveal fatty infiltration and structural changes of mitochondria, though this is not necessary for clinical diagnosis. In addition, abnormal enlargement of the heart (cardiomegaly) associated with cardiomyopathy may be apparent upon chest x-ray examination.
Prenatal diagnosis is available by enzyme measurement of either cultured cells or cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). (With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta.)
Disease management and treatment are primarily directed toward preventing and controlling acute episodes. Preventive measures include avoiding fasting for more than 10 to 12 hours and maintaining a low-fat, high-carbohydrate diet, with frequent feeding (i.e., to keep periods of fasting to a minimum). Additional recommendations may include the use of low-fat nutritional supplements, medium-chain triglycerides (e.g., MCT oil), and corn starch (e.g., at bedtime). Physicians may also advise supplementation with carnitine (Carnitor) and/or riboflavin.
If hospitalized for an acute episode, treatment may require the prompt administration of intravenous glucose (10% dextrose) and additional supportive measures as necessary.
Genetic counseling will also be of benefit for affected individuals and their families. In addition, as noted above, diagnostic testing of siblings is crucial to help detect and appropriately manage the condition. Other treatment for this disorder is symptomatic and supportive.
A clinical trial is currently being conducted on treatment of VLCADD with triheptanoin, an artificial fat that is substituted for MCT oil in the diet. Published studies to date indicate improved glucose control and reduced episodes of rhabdomyolis in patients treated with triheptanoin. Cardiomyopathy may also be improved.
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: [email protected]
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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