Clinical characteristics.

Deficiency of very long-chain acyl-coenzyme A 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 provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms.

Diagnosis/testing.

The diagnosis of VLCAD deficiency is established in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or by identification of biallelic pathogenic variants in ACADVL on molecular genetic testing. If one ACADVL pathogenic variant is found and suspicion of VLCAD deficiency is high, specialized biochemical testing using cultured fibroblasts or lymphocytes may be needed for confirmation of the diagnosis.

Management.

Treatment of manifestations:

• Routine daily treatment. Low-fat formula or low long-chain fat / high medium-chain triglyceride (MCT) medical food, with 13%-39% of calories as total fat; total dietary protein above the dietary reference intake for age; MCT oil or triheptanoin supplementation; carnitine supplementation; consider supplementation with linoleic acid, arachidonic acid, alpha-linolenic acid, and docosahexaenoic acid; frequent feeding in infants and a bedtime snack high in complex carbohydrates in children and adults; nasogastric tube feeding for those with feeding issues; guided exercise and avoidance of severe exercise to address exercise intolerance in older individuals; standard treatment of cardiomyopathy; supportive developmental therapies as needed.
• Emergency outpatient treatment. Consider a trial outpatient treatment at home for up to 12 hours, including frequent high carbohydrate feedings, reduced fasting duration time, antipyretics, and antiemetics.
• Acute inpatient treatment. Administration of high-energy fluids (≥10% IV dextrose) with electrolytes at a rate of at least 1.5 times maintenance (minimum of 8 mg/kg/min of glucose) while avoiding the use of L-carnitine and IV lipids; standard treatment for cardiomyopathy / cardiac failure; ample hydration and alkalization of the urine for those with rhabdomyolysis.

Prevention of secondary complications: Acute rhabdomyolysis is treated with ample hydration and alkalization of the urine to protect kidney function and to prevent acute kidney failure secondary to myoglobinuria; if a surgery or procedure is required, notify designated metabolic center in advance of the procedure to discuss perioperative management with surgeons and anesthesiologists; some anesthetics may be contraindicated.

Surveillance: Measurement of growth parameters (including head circumference) and assessment of feeding skills (in infants/toddlers) at each visit; plasma carnitine panel, acylcarnitine profile, and creatine kinase level every three months for the first year of life, every three to six months for those between age one and seven years, and every six to 12 months for those older than age seven years; red blood cell or plasma essential fatty acids every six months for those on long-chain fat restriction; measurement of vitamins A, D, and E annually or as clinically indicated for those on long-chain fat restriction; echocardiogram at least annually or as clinically indicated; DXA scan every five years in adults; measurement of complete blood count, ferritin level, comprehensive metabolic panel, troponin, and B-type natriuretic protein as clinically indicated.

Agents/circumstances to avoid: Fasting; myocardial irritation; dehydration; high-fat diet; and volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate.

Evaluation of relatives at risk: Evaluation of all at-risk sibs of any age is warranted to identify those who would benefit from treatment and preventive measures.

Pregnancy management: Labor and postpartum periods are catabolic states and place the mother at higher risk for rhabdomyolysis and subsequent myoglobinuria. A management plan for labor and delivery is necessary for the affected pregnant woman. In addition to regular assessment by a cardiologist and maternal fetal medicine specialist, the following are recommended: visit with a nutritionist familiar with VLCAD deficiency monthly or at least in each trimester; measurement of plasma carnitine panel (total, free, esters) and creatine kinase level at each visit; plasma acylcarnitine profile weekly to monthly; red blood cell or plasma essential fatty acids (for those on long-chain fat restriction) at least once during pregnancy; echocardiogram either prior to conception or as soon as a pregnancy is recognized; measurement of vitamins A, D, and E (for those on long-chain fat restriction), complete blood count, ferritin level, and metabolic panel as a baseline or as clinically indicated.

Genetic counseling.

VLCAD deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ACADVL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Molecular genetic carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variants in the family are known.

Suggestive Findings

Establishing the Diagnosis

The diagnosis of VLCAD deficiency is established in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or biallelic pathogenic (or likely pathogenic) variants in ACADVL identified on molecular genetic testing (see Table 1). If one ACADVL pathogenic variant is found and suspicion of VLCAD deficiency is high, specialized biochemical testing using cultured fibroblasts or lymphocytes may be needed for confirmation of the diagnosis.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic ACADVL variants of uncertain significance (or of one known ACADVL pathogenic variant and one ACADVL variant of uncertain significance) does not establish or rule out the diagnosis.

Clinical Description

Depending on the severity of very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency, individuals can present with hypoketotic hypoglycemia, hepatomegaly, cardiomyopathy, and myopathy with recurrent rhabdomyolysis, triggered by a catabolic state. Therefore, the condition has been divided into three clinical subgroups, including a severe early-onset cardiac and multiorgan failure form, a hepatic or hypoketotic hypoglycemic form, and a later-onset myopathic form [Andresen et al 1999]. Most affected individuals identified by newborn screening (NBS) are asymptomatic at the time of diagnosis [Spiekerkoetter 2010, Baruteau et al 2013].

Scenario 1: Abnormal NBS result and prompt initiation of appropriate management in neonatal period. With early intensive supportive care and diet modification (see Management), normal cognitive outcome has been reported.

• Developmental and intelligence quotient (IQ) scores were similar to those seen in the general population (developmental quotient / IQ ≥85) [Brown et al 2014, Landau et al 2017].
• However, motor and speech delays were reported [Waisbren et al 2013].

Both Pena et al [2016] and Vockley et al [2016] reported individuals who developed cardiomyopathy while being treated with a medium-chain triglyceride oil-based diet.

Bleeker et al [2019] and Marsden et al [2021] reported that NBS results in prevention of hypoglycemic events in those with some residual enzyme activity, but not prevention of hypoglycemia or cardiac complications in affected individuals with very low residual enzyme activity.

Scenario 2: Symptomatic individual associated with later-onset VLCAD deficiency or untreated infantile-onset VLCAD deficiency (resulting from NBS not performed or false negative NBS result)

• 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 may be reversible with early intensive supportive care and diet modification.
  • Cox et al [1998] reported normal cognitive outcome at age four years in an affected individual diagnosed clinically with VLCAD deficiency who had severe hypertrophic cardiomyopathy at age five months.
• Hepatic or hypoketotic hypoglycemic VLCAD deficiency typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly (similar to medium-chain acyl-coenzyme A dehydrogenase deficiency) but without cardiomyopathy. Hypoglycemia and poor feeding during the newborn period have been reported in neonates who were later diagnosed with VLCAD deficiency [Pena et al 2016].
• Later-onset episodic myopathic VLCAD deficiency, probably the most common phenotype, presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptom onset in these individuals. Ascertainment in adulthood has been reported [Hoffman et al 2006].

Genotype-Phenotype Correlations

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

• Severe disease is associated with no residual enzyme activity, often resulting from null variants. Approximately 81% of pathogenic truncating variants in ACADVL are associated with the severe early-onset form [Andresen et al 1999].
• A specific homozygous missense pathogenic variant (c.709T>C;p.Cys237Arg) leading to low long-chain fatty acid oxidation flux may also be associated with cardiac disease [Diekman et al 2015].
• Milder childhood and adult forms are often associated with residual enzyme activity. The common p.Val283Ala variant, in both homozygous and compound heterozygous genotypes, is typically associated with the non-cardiac phenotypes [Spiekerkoetter et al 2009, Diekman et al 2015, Miller et al 2015].

Prevalence

Complete ascertainment by NBS is not assured, but the incidence of VLCAD deficiency is now estimated at 1:30,000 to 1:100,000 births.

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

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with VLCAD deficiency, the evaluations summarized in Tables 4 or 5 (depending on the age at diagnosis) are recommended, if not previously performed as part of the evaluation that led to the diagnosis.

Treatment of Manifestations

Frequently updated, succinct emergency care plans should detail the typical clinical issues (either those already experienced by the affected individual 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 of rhabdomyolysis) and avoidance of triggers (fasting, long-chain fats, and irritation of the myocardium) [Arnold et al 2009].

Cardiac dysfunction may be reversible with early, intensive supportive care (occasionally including extracorporeal membrane oxygenation) and diet modification.

Triheptanoin (C7). This odd medium-chain fatty acid was approved by the FDA in June 2020 for the treatment of pediatric and adult individuals with VLCAD deficiency.

• The use of triheptanoin is based on its action as an anaplerotic molecule that can correct the secondary depletion of TCA cycle intermediates occurring in these disorders.
• Benefits include decrease in total days of hospitalization per year and reduction in episodes of rhabdomyolysis [Roe & Brunengraber 2015, Zöggeler et al 2021]. Improvement in cardiomyopathy, hepatomegaly, and hypoglycemia was reported in those treated with triheptanoin compared to pretreatment [Roe & Brunengraber 2015, Vockley et al 2015, Vockley et al 2016, Gillingham et al 2017, Vockley et al 2017, Calvert et al 2018].
• Triheptanoin was less effective in reducing rhabdomyolysis post treatment compared to its effect on other symptoms of VLCAD deficiency, suggesting a role for other pathophysiologic mechanisms and demonstrating the need for additional therapies (see Therapies Under Investigation) [Sklirou et al 2021].
• Adverse events in all of the clinical trials were similar for C7 and C8 treatment and predominantly consisted of gastrointestinal symptoms (abdominal pain, diarrhea) [Sklirou et al 2021, Zöggeler et al 2021].

Transitional care from pediatric to adult-centered multidisciplinary care settings. As a lifelong disorder with varying implications according to age, smooth transition of care from the pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Standardized procedures for transitional care do not exist for VLCAD deficiency because of the absence of multidisciplinary outpatient departments.

• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with VLCAD deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.

Prevention of Primary Manifestations

See Management, Treatment of Manifestations, Table 6.

Prevention of Secondary Complications

One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation results in management that can be administered expediently in the setting of intercurrent illness or other catabolic stressors.

Surveillance

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the surveillance evaluations summarized in Table 11 are recommended.

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. Careful weight reduction has been accomplished by restricting long-chain fats and calories, supplementing with calories provided through medium-chain triglycerides, and limiting overnight catabolism with uncooked cornstarch [Zweers et al 2012].
• Volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate [Vellekoop et al 2011]. However, the use of propofol for short-duration procedures has been evaluated in individuals with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency and was not found to cause adverse events [Martin et al 2014].

Evaluation of Relatives at Risk

Testing of all at-risk sibs of any age is warranted to identify as early as possible those who would benefit from institution of treatment and preventive measures (see Management, Treatment of Manifestations).

• If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known, plasma or dried blood spot acylcarnitine analysis may not be sufficiently sensitive, and direct VLCAD assay of lymphocytes or fatty acid oxidation probe studies of cultured fibroblasts may be required.

For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening either test for the familial ACADVL pathogenic variants or measure an acylcarnitine profile.

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 postpartum 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].

Energy needs and fat intake recommendations for women who are pregnant or lactating are listed in Table 7.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Bezafibrates. Small clinical trials have demonstrated controversial results.

• An open-label clinical trial showed continuously improving physical functioning as assessed through quality of life questionnaire scores in all affected individuals who participated [Shiraishi et al 2019].
• An in vitro study found that mitochondrial metabolic capacity and glutathione were affected by benzafibrate treatment [Lund et al 2021].

Dodecanedioic acid. In an in vitro study, dodecanedioic acid supplementation reduced levels of toxic very long-chain acylcarnitines [Radzikh et al 2021].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an ACADVL pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ACADVL pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an ACADVL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has VLCAD deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ACADVL.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ACADVL pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the ACADVL pathogenic variants in the family.

Biochemical genetic testing. Measurement of acylcarnitines (an acylcarnitine profile), particularly in an unstressed individual, is not reliable for identifying heterozygotes. 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 previously, but in most cases molecular genetic testing is preferred. In addition, the clinical availability of the VLCAD enzyme assay has varied with time.

Related Genetic Counseling Issues

The genetic status of full sibs should be determined since many individuals with VLCAD deficiency are not symptomatic during early childhood. See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis, treatment, and preventive measures.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the ACADVL pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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 (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 and clinical availability of these assays is limited in the United States, molecular genetic testing is preferred for prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The fatty acid oxidation (FAO) spiral is a series of four reactions occurring in the mitochondrial matrix. Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation (β-oxidation) of long-chain fatty acids with a chain length of 14 to 20 carbons. There are a total of four highly homologous, straight-chain acyl-coenzyme A (CoA) dehydrogenases with differing, but overlapping, substrate specificities:

• Short (SCAD; 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.

With every turn of the β-oxidation spiral, the chain length is shortened by two carbon atoms. Reactions distal to the long-chain acyl-CoA dehydrogenase (LCAD) include those catalyzed by the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) / trifunctional protein, including a hydratase step, dehydrogenase step, and thiolase step.

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, maintain cardiac output, adapt to long fasting, and generate energy for exercise.

Mechanism of disease causation. Loss of function

Author History

Jessica A Connor, MS; Counsyl, Inc (2014-2017)
Nancy D Leslie, MD (2009-present)
Sofia Saenz-Ayala, MD (2022-present)
Kerry Shooner, MS, CGC; Cincinnati Children's Hospital Medical Center (2009-2014)
Arnold W Strauss, MD; Cincinnati Children's Hospital Medical Center (2009-2022)
Brad T Tinkle, MD, PhD; Cincinnati Children's Hospital Medical Center (2009-2014)
C Alexander Valencia, PhD; Cincinnati Children's Hospital Medical Center (2014-2022)
Kejian Zhang, MD, MBA; Cincinnati Children's Hospital Medical Center (2009-2022)

Revision History

• 13 July 2023 (nl) Revision: C14:1 level unit of measurement corrected to µmol/L in Suggestive Findings
• 16 June 2022 (ma) Comprehensive update posted live
• 4 January 2018 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 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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