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Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Synonyms: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency, VLCAD Deficiency

, MD, , MD, PhD, , MD, , MS, CGC, and , MD, MBA.

Author Information
, MD
Clinical and Metabolic Geneticist, Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
, MD, PhD
Clinical and Clinical Molecular Geneticist, Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
, MD
Chair, Department of Pediatrics
University of Cincinnati
Chief Medical Officer, Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
, MS, CGC
Genetic Counselor, Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
, MD, MBA
Associate Professor of Clinical Pediatrics, Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio

Initial Posting: ; Last Update: September 22, 2011.

Summary

Disease characteristics. Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms.

Diagnosis/testing. Diagnosis relies on (1) comprehensive acylcarnitine analysis by tandem mass spectrometry of plasma or a dried blood spot specimen collected during a period of metabolic stress (especially fasting or reduced caloric intake during infectious illness or procedures), followed by (2) molecular genetic testing of ACADVL, the only gene in which mutations are known to cause VLCAD deficiency. Additional diagnostic tests are functional analysis of fatty acid oxidation in cultured fibroblasts and measurement of VLCAD enzyme activity in fibroblasts or lymphocytes.

Management. Treatment of manifestations: Use of IV glucose as an energy source, treatment of cardiac rhythm disturbance, and monitoring for rhabdomyolysis. Cardiac dysfunction is reversible with early, intensive supportive care (occasionally including extra-corporeal membrane oxygenation) and diet modification.

Prevention of primary manifestations: Individuals with the more severe forms are typically placed on a low-fat formula, with supplemental calories provided through medium-chain triglycerides (MCT).

Prevention of secondary complications: Acute rhabdomyolysis is treated with ample hydration and alkalization of the urine to protect renal function and to prevent acute renal failure secondary to myoglobinuria.

Agents/circumstances to avoid: Fasting, myocardial irritation, dehydration, and high fat diet.

Evaluation of relatives at risk: Timely evaluation of older and younger sibs of a proband to identify those who would benefit from institution of treatment and preventive measures.

Genetic counseling. VLCAD deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons. VLCAD deficiency is associated with a range of phenotypes, including:

  • Severe early-onset cardiac and multiorgan failure form
  • Hepatic or hypoketotic hypoglycemic form
  • Later-onset episodic myopathic form

Testing

Acylcarnitine analysis. Plasma or dried blood spot comprehensive acylcarnitine analysis using tandem mass spectrometry and measuring C4-C20 straight-chain acyl-carnitine esters, 3-hydroxy-acyl carnitine esters, and unsaturated acyl-carnitine esters is most sensitive when collected during a period of metabolic stress, such as fasting. The key metabolites that are most often abnormal in VLCAD deficiency are C14:1, C14:2, C14, and C12:1 [McHugh et al 2011].

  • Although cut-off/abnormal values vary by age, method of collection, and laboratory, a C14:1 level greater than 1 mmol/L on an initial newborn screening test strongly suggests VLCAD deficiency. Individuals with this level should be assumed to have VLCAD deficiency.
  • Levels of C14:1 greater than 0.8 mmol/L suggest VLCAD deficiency but may also occur in carriers and some healthy individuals having no ACADVL mutations.

Note: (1) Diagnostic abnormalities may no longer be present if an individual has been fed or has been treated with an IV glucose infusion or if the episode prompting concern has resolved. (2) Newborn screening data have affirmed that acylcarnitine analysis during physiologic wellness often fails to identify affected individuals who have the milder phenotypes. (3) Depending on the “cut-off” limits used, initial acylcarnitine screening often detects heterozygotes (i.e., carriers).

Analysis of fatty acid ß-oxidation in cultured fibroblasts. In vitro incubation of cultured fibroblasts with C13-palmitate or unlabeled palmitate and carnitine may provide indirect evidence of deranged beta-oxidation. Individuals with severe VLCAD deficiency typically accumulate excess tetradecanoyl (C14) carnitine, whereas individuals with less severe phenotypes may shift accumulation toward dodecanoyl (C12) carnitine. This test isoften called the “in vitro probe study.”

Analysis of VLCAD enzyme activity. Measurement VLCAD enzyme activity in leukocytes, cultured fibroblasts, liver, heart, skeletal muscle, or amniocytes by the electron transfer flavoprotein or ferricineum reduction assay can be used to confirm the diagnosis of VLCAD deficiency. Better specificity has been noted when the products are separated and quantitated by HPC or MS/MS.

Immunoreactive VLCAD protein antigen expression (an “immunoblot”). This test uses polyclonal, specific antibodies to make a semi-quantitative assessment of expressed VLCAD antigen levels in protein extracts derived from cultured fibroblasts. Levels lower than 10% of control are consistent with VLCAD deficiency.

Molecular Genetic Testing

Gene. ACADVL is the only gene in which mutations are known to cause VLCAD deficiency.

Clinical testing

  • Sequence analysis of all 20 exons and exon/intron boundaries of ACADVL detects mutations in 85%-93% of persons with VLCAD deficiency. Among individuals with clinical disease, Andresen et al [1999] found mutations in both ACADVL alleles in the index case of 47 of 55 families (94 of 110 alleles; 85%). In the remaining eight index cases, an ACADVL mutation was detected in only one of the two alleles. These cases may represent the current limits of sensitivity for sequence analysis.

    Note: Exonic, multiexonic and whole-gene deletions and insertions are not identified by this method (see Deletion/duplication analysis).
  • Deletion/duplication analysis identifies deletions and duplications of one or more exons or the whole gene. The frequency of large deletions or duplications appears low.

Table 1. Summary of Molecular Genetic Testing Used in VLCAD Deficiency

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ACADVLSequence analysisSequence variants 4Two mutations in 47/55 and one mutation in 8/55 families with clinical disease 5
Deletion/duplication analysis 6(Multi)exonic and whole-gene deletions/duplicationsUnknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Andresen et al [1999]

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods may be used including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific). A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.

Interpretation of test results. In vitro functional assays have been developed to characterize mutations and understand how they cause the clinical aspects of the disease (see Molecular Genetics, Pathogenic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Acylcarnitine profile on analysis of plasma or a dried blood spot. Molecular genetic analysis is probably indicated in all individuals with levels higher than 0.8 mmol/L [Liebig et al 2006].
  • ACADVL molecular genetic testing (sequence analysis, followed by deletion/duplication analysis if neither or only one mutation is identified):
    • If two deleterious ACADVL mutations are found, a presumptive diagnosis of VLCAD deficiency is made.
    • If one ACADVL mutation is found, functional assessment of beta-oxidation or direct VLCAD enzyme activity assay using protein extracts from cultured fibroblasts or lymphocytes is recommended.

      Note: Skin biopsy for studies on cultured fibroblasts is often obtained while awaiting molecular studies if suspicion of VLCAD deficiency is high. Cultured fibroblasts can be assessed for in vitro beta oxidation and acylcarnitine profiling [Roe et al 2001], direct assay of VLCAD enzyme activity, and assessment of immunoreactive VLCAD protein.
    • If no ACADVL mutations are found, VLCAD deficiency is highly unlikely and consideration should be given to other disorders of long-chain fatty acid oxidation (see Differential Diagnosis).

Population-based newborn screening using MS/MS technology has identified numerous affected individuals [Boneh et al 2006].

  • All abnormal results on newborn screening should be followed by a confirmatory acylcarnitine profile as well as molecular genetic testing [Boneh et al 2006, Image ACMGalg.jpg].

    Note: A majority of individuals with an abnormal newborn screen have one ACADVL mutation and are likely heterozygotes (i.e., carriers) detected because of the high sensitivity of the initial acyl-carnitine screening assay.
  • Skin biopsy and culture of skin fibroblasts for assessment of β-oxidation of palmitate, enzyme assay of VLCAD activity, and/or immunoquantification of VLCAD antigen are also recommended.

Postmortem testing. The following have been used to identify FAO disorders postmortem:

  • Biochemical testing of liver or bile for acylcarnitine elevations and histochemical analysis for microvesicular steatosis
  • Studies on a post-mortem skin biopsy
  • Elevated concentrations of C8-C16 free fatty acids in plasma
  • Plasma or dried blood spot acyl-carnitine analyses by MS/MS

If these analyses are suspicious, retrospective molecular genetic and biochemical testing of newborn blood spots can often be performed to confirm a diagnosis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Three clinical groups of VLCAD deficiency have been reported [Andresen et al 1999].

Severe early-onset cardiac and multiorgan failure VLCAD deficiency typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia.

Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [Bonnet et al 1999]. Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction is reversible with early intensive supportive care and diet modification; normal cognitive outcome has been reported in these individuals.

Hepatic or hypoketotic hypoglycemic VLCAD deficiency typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly (similar to MCAD deficiency) but without cardiomyopathy. Individuals with hypoglycemia associated with a large quantity of ketones on urine dipstick testing are less likely to have impairment of the fatty acid oxidation spiral than those with small or undetectable quantity of ketones, but ketones may be present in either group.

Later-onset episodic myopathic VLCAD deficiency presents with intermittent rhabdomyolysis, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms.

Ascertainment in adulthood has been reported [Hoffman et al 2006]. This is probably the most common phenotype.

Pathophysiology. The fatty acid oxidation (FAO) spiral is a series of four reactions occurring in the mitochondrial matrix. The first step is catalyzed by four highly homologous, straight-chain acyl-CoA dehydrogenases with differing, but overlapping, substrate specificities:

  • Short (SCAD that uses C4-C6 fatty acyl-CoAs)
  • Medium (MCAD; C6-C10 fatty acyl-CoAs)
  • Long (LCAD; C10-C14 fatty acyl-CoAs)
  • Very long (VLCAD; C14-C20 fatty acyl-CoAs)

SCAD, MCAD, and LCAD are homotetramers localized to the mitochondrial matrix; VLCAD is a homodimer associated with the inner mitochondrial membrane. These four homologs share about 40% amino acid identity or similarity within the catalytic domain; all use flavin adenine dinucleotide as the electron-accepting cofactor. Electrons are fed into the electron transport chain via ETF and ETF dehydrogenase.

The use of fat to supply energy is important at critical points of physiologic adaptation. In utero, the fetus derives a constant supply of energy from glucose supplied continuously via the placenta. Following birth, maternal milk in which about 60% of calories are fat becomes the major nutrient, and therefore, fat becomes the major energy source, especially in the heart and other highly oxidative organs such as kidney and skeletal muscle [Hale et al 1985, Aoyama et al 1993].

The heart constantly uses fatty acids for energy. In contrast, the liver uses nutrients delivered directly during the absorptive phase of digestion and controls the short- and medium-term storage and distribution of energy from glycogenolysis and gluconeogenesis. However, during longer periods of fasting, the liver uses acetyl CoA to generate ketone bodies. The brain adapts to fasting by switching to a ketone economy, reducing the need for glucose as the energy source. With exercise, especially prolonged exercise, slow skeletal muscles use longer chain FAO to generate energy. In summary, the adaptation to fasting depends on the supply of energy, the rate of consumption and preferred substrate, and physiologic backup mechanisms to provide alternative sources of energy in times of stress or transition.

As one of the first enzymes in the FAO spiral, the enzyme VLCAD controls a critical point in the supply of electrons to the respiratory chain, and also provides a pathway permissive to the production of ketones. It would be expected that significant reduction at this step of fatty acid oxidation would impair the ability to transition successfully from fetal to neonatal life, to maintain cardiac output, to adapt to long fasting, and to generate energy for exercise. All of the above difficulties have been observed in VLCAD deficiency. The most severe defects result in early-infantile cardiomyopathy, hepatomegaly, hypotonia, and intermittent hypoglycemia.

Genotype-Phenotype Correlations

As a general rule, a strong genotype-phenotype correlation exists in VLCAD deficiency [Andresen et al 1999]:

  • Severe disease is associated with no residual enzyme activity, often resulting from null mutations.
  • Milder childhood and adult forms are often associated with residual enzyme activity, resulting from one or two missense mutations. The common Val243Ala mutation has usually been associated with the mild phenotype [Spiekerkoetter et al 2009].

Penetrance

Severe forms are suspected to be fully penetrant.

Since the later-onset forms may have vague or intermittent symptoms, it is possible that some individuals may have no symptoms during their lifetime.

Nomenclature

When the severe phenotype of VLCAD deficiency was described initially by Hale et al [1985], it was attributed to deficiency of the enzyme LCAD. The correct identification of the deficient enzyme, VLCAD, was made by Aoyama et al [1993].

Prevalence

Complete ascertainment by newborn screening is not assured, but the incidence of VLCAD deficiency is now suspected to be 1:30,000 in the US. Currently, more than 400 cases have been reported [McHugh et al 2011].

Newborn screening has demonstrated that VLCAD deficiency is more prevalent than previously suspected; however, the majority of children ascertained by newborn screening are asymptomatic during the few years of observation, suggesting that these individuals may have gone undiagnosed prior to the advent of population-based screening.

Differential Diagnosis

Infantile cardiomyopathy with evidence of abnormal fatty acid oxidation may be seen in [Roe et al 2006]:

  • Carnitine uptake disorder
  • Severe carnitine palmitoyltransferase II (CPT II) deficiency
  • Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/ trifunctional protein deficiency.
  • Carnitine-acylcarnitine translocase deficiency
  • Severe forms of multiple acyl-CoA dehydrogenase deficiency

The hepatic “hypoglycemic” form may be similar to medium-chain acyl CoA dehydrogenase (MCAD) deficiency or the electron transfer flavoprotein (ETF)/ETF ubiquinone (coenzyme Q) oxidoreductase defects which produce multiple acyl-CoA dehydrogenase deficiencies.

Intermittent rhabdomyolysis is a feature of McArdle disease, CPT II deficiency, some primary myopathies, and trifunctional protein deficiency.

A variety of cardiac, liver, brain, and muscle phenotypes were seen in the three published cases of ACAD9 deficiency, a newly described disorder involving oxidation of long-chain fatty acyl CoAs [He et al 2007].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with VLCAD deficiency, the following evaluations are recommended:

  • Measurement of baseline plasma (serum) creatine kinase (CK) concentration
  • Measurement of baseline liver transaminases
  • Cardiac echocardiography
  • Electrocardiogram
  • Genetics consultation

Note: In the setting of acute disease, measurement of blood glucose concentration and blood ammonia concentration may be indicated.

Treatment of Manifestations

Frequently updated, succinct “emergency” care plans should detail the typical clinical issues (either those already experienced by the patient or those anticipated based on the diagnosis) and the importance of early management (e.g., use of IV glucose as an energy source, monitoring for cardiac rhythm disturbance, and monitoring for rhabdomyolysis), and avoidance of triggers (fasting, long-chain fats, and irritation of the myocardium) [Arnold et al 2009].

Cardiac dysfunction is reversible with early, intensive supportive care (occasionally including extra-corporeal membrane oxygenation) and diet modification. See Prevention of Primary Manifestations.

Prevention of Primary Manifestations

Individuals with the more severe forms are typically placed on a low-fat formula, with supplemental calories provided through medium-chain triglycerides (MCT). A variety of strategies for the low-fat diet are used, ranging from 13%-39% of calories as total fat, with an additional 15%-18% of calories supplied as MCT oil in those most strictly restricted for long-chain fats [Solis & Singh 2002].

Extra MCT has demonstrated benefit in older individuals with long-chain defects who have exercise intolerance. Gillingham et al [2006] demonstrated improved exercise tolerance in individuals given 0.5 g/kg lean body weight 20 minutes prior to exercise. Only individuals with LCHAD and TFP deficiencies were formally studied.

Triheptanoin has been used in a few individuals with the goal of providing calories as well as providing anaplerotic carbons; however, the efficacy remains controversial.

Severe exercise (e.g., military training) has unmasked symptoms in previously asymptomatic adults [Hoffman et al 2006, Laforêt et al 2009], emphasizing that exercise should be guided by the individual’s tolerance level.

The use of carnitine supplementation is controversial [Arnold et al 2009]: consensus as to whether additional carnitine is detrimental or efficacious has not been established.

Prevention of Secondary Complications

Acute rhabdomyolysis is treated with ample hydration and alkalization of the urine to protect renal function and to prevent acute renal failure secondary to myoglobinuria.

Agents/Circumstances to Avoid

Avoid the following:

  • Fasting, including periods of preparation and recovery from planned surgery or sedation [Vellekoop et al 2011].
  • Myocardial irritation (e.g., cardiac catheterization)
  • Dehydration (risk for acute tubular necrosis)
  • High-fat diet (long-chain fats) including ketogenic or carbohydrate restricted diets for the purpose of weight loss
  • Volatile anesthetics and those that contain high doses of long-chain fatty acids such as propofol and etomidate [Vellekoop et al 2011].

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

During pregnancy, placental and fetal beta-oxidation may temporize or even improve maternal fatty acid beta-oxidation [Mendez-Figueroa et al 2010]. However, labor and post-partum periods are catabolic states and place the mother at higher risk for rhabdomyolysis and subsequent myoglobinuria. A management plan for labor and delivery has been proposed by Mendez-Figueroa et al [2010].

Therapies Under Investigation

Triheptanoin is a source of 7-carbon fatty acids which may be superior to medium-chain triglycerides, in that they provide a 3-carbon chain to promote anaplerosis [Roe et al 2002].

Bezafibrate, a PPAR pan agonist, has been shown to increase VLCAD enzyme activity in vitro in fibroblasts cultured from individuals with ACADVL missense mutations [Djouadi et al 2005, Gobin-Limballe et al 2007]. It is not known whether this observation translates into reduction of clinical morbidity.

Dantrolene sodium, a muscle relaxant, may be useful as an adjunctive therapy in adult-onset rhabdomyolysis [Voermans et al 2005].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

VLCAD deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • The genetic status of full siblings should be determined, since many individuals with VLCAD deficiency are not symptomatic during early childhood.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with VLCAD deficiency are obligate heterozygotes (carriers) for an ACADVL disease-causing mutation.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Biochemical genetic testing. The carrier status increases the likelihood of detection in a newborn screening program, as individuals with half of the normal VLCAD enzyme activity may have acylcarnitine levels near the upper limits of the normal range and the lower limits of the “possibly affected” range, particularly under the conditions of stress imposed by perinatal transition. However, testing of acylcarnitines, particularly in the unstressed individual, is not a reliable test for heterozygote status.

Functional testing of fibroblasts, using the various protocols of palmitate oxidation and incorporation into small acylcarnitine species, also does not typically identify carriers.

A direct VLCAD enzyme assay may provide better evidence of a carrier state than the options described above, but in most cases, molecular genetic testing is preferred.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individual.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Biochemical genetic testing. Prenatal diagnosis of VLCAD deficiency based on the pattern of incorporation of labeled carbons (ranging from palmitate into shorter chain acylcarnitines) by cultured amniocytes that is similar to the fibroblast in vitro acylcarnitine profile has been described. Assay of VLCAD enzyme activity can distinguish between affected and unaffected cells. Absence of immunoreactive VLCAD on Western blot analysis in those with severe VLCAD deficiency should provide additional information. As experience with these techniques is limited in the US, molecular genetic testing is preferred for prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (View All in OMIM)

201475ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN, DEFICIENCY OF; ACADVLD
609575ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN; ACADVL

Molecular Genetic Pathogenesis

Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons.

Normal allelic variants. See Table 2. ACADVL comprises 20 exons spanning approximately 5.4 kb. Normal allelic variants are few and primarily only tolerated outside of the conserved domain, which spans from approximately amino acid 70 through 480.

In addition, an exonic sequence substitution, p.Pro65Leu, results in an N-terminal in-frame splicing variant known as [increment]Ex3 VLCAD, which is missing 22 amino acids (residues 7-28 of the mature protein). In vitro studies have shown that the protein product of the [increment]Ex3 VLCAD splice variant is stable with very high specific activity and substrate profile comparable to the wild type VLCAD [Watanabe et al 2000, Spiekerkoetter et al 2003].

Pathogenic allelic variants. See Table 2. Hundreds of pathogenic mutations are known, including consensus splice-site mutations causing missplicing, short coding region duplications and deletions altering the reading frame, premature termination codon mutations, and many missense mutations that occur throughout the VLCAD protein.

One of the most common pathogenic alleles, c.848T>C where valine is substituted for alanine at codon position 283, is observed in symptomatic compound heterozygotes and in homozygotes. It accounts for approximately 20% of all pathogenic alleles among individuals detected by newborn screening.

The remaining pathogenic variants have often been reported as recurring but their overall frequency is not well established.

Racial and ethnic variants are reported; p.Thr409Met, for example, is observed more commonly among individuals of Pacific Island ancestry than in other populations.

In vitro functional assays have been used in the research laboratory setting to characterize putative missense mutations and to investigate the clinical and biochemical aspects of VLCAD deficiency [Gobin-Limballe et al 2007, Goetzman et al 2007].

Table 2. Selected ACADVL Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
Normalc.49C>Tp.Leu17PheNM_000018​.2
NP_000009​.1
c.68G>Ap.Arg23Gln
c.128G>A p.Gly43Asp
c.194C>Tp.Pro65Leu 2
c.1038G>Ap.Ala346Ala
Pathogenicc.848T>Cp.Val283Ala
(Val243Ala)
c.779C>Tp.Thr260Met
(Thr220Met)
c.1226C>Tp.Thr409Met
(Thr369Met)
c.1322G>Ap.Gly441Asp
(Gly401Asp)
c.1405C>Tp.Arg469Trp
(Arg429Trp)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions. Note: Earlier references used protein nomenclature consistent with the mature protein and are provided in parentheses.

2. See Normal allelic variants.

Normal gene product. The mature protein of 615 amino acids has a large, tightly conserved functional domain common to the acyl-CoA dehydrogenases. The major isoform encodes a precursor protein of 655 amino acids with a mitochondrial targeting sequence of 40 amino acids that is removed during uptake, resulting in the mature membrane-associated protein of 615 amino acid residues as reported by Aoyama et al [1995] and Strauss et al [1995].

Abnormal gene product. The majority of abnormal (i.e., pathogenic) gene products result from missense mutations, with reduced enzyme activity and/or reduced stability leading to lower steady state levels in mitochondria.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Suggested Reading

  1. Schuler AM, Gower BA, Matern D, Rinaldo P, Vockley J, Wood PA. Synergistic heterozygosity in mice with inherited enzyme deficiencies of mitochondrial fatty acid beta-oxidation. Mol Genet Metab. 2005;85:7–11. [PubMed: 15862275]

Chapter Notes

Revision History

  • 22 September 2011 (me) Comprehensive update posted live
  • 28 May 2009 (me) Review posted live
  • 29 December 2008 (ks) Original submission
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