Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid beta-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality, and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. Ages of onset described in the paper are <3 d, 1-11 m, 1-4 y, >13 y (PMID:9973285). VLCAD deficiency is an autosomal recessive disorder due to deficiency in the VLCAD enzyme located on the inner mitochondrial membrane. The enzyme catalyses the initial step of mitochondrial beta-oxidation of long-chain fatty acids which is crucial for energy production in heart and skeletal muscles (PMID:24044064).
Over 400 cases have been reported worldwide. Prevalence in Germany is of 1/50, 000 (Orphanet, May 2016).
Inborn errors of mitochondrial fatty acid beta-oxidation include medium-chain acyl-CoA dehydrogenase deficiency (201450), short-chain acyl-CoA dehydrogenase deficiency (201470), and very long-chain acyl-CoA dehydrogenase deficiency.
VLCAD deficiency can be classified clinically into 3 forms: a severe early-onset ... Inborn errors of mitochondrial fatty acid beta-oxidation include medium-chain acyl-CoA dehydrogenase deficiency (201450), short-chain acyl-CoA dehydrogenase deficiency (201470), and very long-chain acyl-CoA dehydrogenase deficiency. VLCAD deficiency can be classified clinically into 3 forms: a severe early-onset form with high incidence of cardiomyopathy and high mortality; an intermediate form with childhood onset, usually with hypoketotic hypoglycemia and more favorable outcome; and an adult-onset, myopathic form with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria after exercise or fasting (Andresen et al., 1999). Patients reported with long-chain acyl-CoA dehydrogenase (LCAD) deficiency before VLCAD deficiency was defined were later found to have VLCAD deficiency (Strauss et al., 1995; Roe and Ding, 2001).
Costa et al. (1996) described 2 patients with celiac disease and prolonged malnourishment whose urinary organic acid profile during a crisis of metabolic decompensation was similar to those frequently observed in long-chain fatty acid oxidation disorders. The first ... Costa et al. (1996) described 2 patients with celiac disease and prolonged malnourishment whose urinary organic acid profile during a crisis of metabolic decompensation was similar to those frequently observed in long-chain fatty acid oxidation disorders. The first patient was a girl with a history of vomiting and poor weight gain since the introduction of solid food at the age of 3 months. Clinically she had failure to thrive, hypotonia, and motor retardation. Metabolic screening at the age of 12 months revealed normal amino acids, purines, pyrimidines, and mono- and oligosaccharides. Urinary organic acid analysis revealed an increased excretion of dicarboxylic (DC) and 3-hydroxydicarboxylic (3OHDC) acids without ketonuria. Celiac disease was suspected because of gastrointestinal problems. On a gluten-free diet, the organic acid profile normalized completely. The second patient, a girl, presented with a similar clinical history. Organic acid analysis from the urine collected at 12 months of age revealed hypoketotic dicarboxylic aciduria. After the diagnosis of celiac disease and the introduction of a gluten-free diet, the organic acid profile normalized completely. Costa et al. (1996) showed that neither the demonstration of hypoketotic dicarboxylic aciduria nor the analysis of the ratios between urinary DC and 3OHDC acids was sufficient grounds to prove a reliable diagnosis of a potential fatty acid oxidation defect. Ohashi et al. (2004) identified 13 patients with the myopathic form of VLCAD deficiency by using immunohistochemistry to analyze the VLCAD protein in skeletal muscle biopsies. Biochemical analysis confirmed that all 13 patients had low enzymatic activity and reduced amounts of VLCAD protein. Genetic analysis confirmed that they all had mutations in the ACADVL gene. Ohashi et al. (2004) concluded that the immunohistochemical technique was an effective diagnostic tool for VLCAD deficiency.
Hale et al. (1985) reported 3 unrelated children who presented in early childhood with nonketotic hypoglycemia and episodes of cardiorespiratory arrest associated with fasting. Other features included hepatomegaly, cardiomegaly, and hypotonia. Total plasma carnitine concentration was low. The ... Hale et al. (1985) reported 3 unrelated children who presented in early childhood with nonketotic hypoglycemia and episodes of cardiorespiratory arrest associated with fasting. Other features included hepatomegaly, cardiomegaly, and hypotonia. Total plasma carnitine concentration was low. The findings suggested a defect in mitochondrial fatty acid oxidation. Specific assays showed that the activity of long-chain acyl-CoA dehydrogenase was less than 10% of control values in fibroblasts, leukocytes, and liver. Activities of medium-chain, short-chain, and isovaleryl CoA dehydrogenases were normal. With cultured fibroblasts, CO2 evolution from medium-chain and short-chain fatty acids was normal and that from long-chain fatty acids was reduced. As in medium-chain acyl-CoA dehydrogenase deficiency, dicarboxylic acids in the urine and relatively low urinary beta-hydroxybutyrate levels were formed by omega-oxidation of fatty acids in the cytoplasm. The parents had intermediate levels of enzyme activity, suggesting autosomal recessive inheritance. Hale et al. (1985) also demonstrated deficiency of the long-chain dehydrogenase in fibroblasts from 2 sibs reported by Naylor et al. (1980) with features similar to those in their 3 patients. Treem et al. (1991) described an affected infant and compared the case with 7 previously published cases. The infant had hypotonia and marked cardiac enlargement as well as hypoglycemia. Ribes et al. (1992) provided follow-up information on a patient described by Riudor et al. (1986). LCAD deficiency had been documented in the fibroblasts from the patient and treatment with frequent low-fat high-carbohydrate feedings, riboflavin, and carnitine reduced the frequency and intensity of crises. However, the patient developed progressive cardiomegaly and persistent hepatosplenomegaly. Following a crisis similar to those suffered previously, he went into cardiorespiratory arrest at the age of 4.5 years. Bertrand et al. (1993) reported deficiency of very long-chain acyl-CoA dehydrogenase in a 2-year-old girl with a fatty acid oxidation defect. Yamaguchi et al. (1993) identified VLCAD deficiency in 3 patients previously diagnosed with LCAD deficiency. Aoyama et al. (1993) reported 2 male patients with VLCAD deficiency as evidenced by in vitro findings of very low palmitoyl-CoA dehydrogenase activity and lack of immunoreactivity to antibody against the VLCAD protein. One patient presented at age 3 months with hypoketotic hypoglycemia, hepatocellular disease, and cardiomyopathy. At autopsy, there was severe hepatocellular injury and marked lipid accumulation in many tissues. The other patient, reported by Tonsgard et al. (1991) as an instance of an unexplained defect of long-chain fatty acid oxidation, presented at age 4 months with hypoglycemia, hepatocellular dysfunction, and cardiomyopathy. Laboratory testing revealed hyperammonemia and increased urinary levels of adipate and sebacate. Microscopic examination at autopsy showed lipid accumulation in many tissues. Ogilvie et al. (1994) reported a 21-year-old man with VLCAD who presented with a 5-year history of exercise-induced muscle pain and myoglobinuria. Residual enzyme activity was approximately 10% of control values. The patient was able to decrease the amount of pain if he ate a carbohydrate snack before or during the exercise. Aoyama et al. (1995) used immunoblotting to analyze for VLCAD protein deficiency in skin fibroblasts from 26 patients suspected of having a disorder of mitochondrial beta-oxidation; 7 samples contained undetectable or trace levels of the VLCAD enzyme. Clinically, all patients with VLCAD deficiency exhibited cardiac disease, and at least 4 of them presented with hypertrophic cardiomyopathy. The biochemical work suggested a heterogeneity of mutations causing deficiency in the 7 patients. Six of the 7 patients studied by Aoyama et al. (1995) were North American Caucasians, and 1 was Asian. Clinical onset of abnormality was within 4 months after birth, 75% died within 2 months after onset, and all patients had liver dysfunction and cardiac disease. Fukao et al. (2001) reported a 14-year-old Japanese girl who presented with recurrent myalgia and elevated serum creatine kinase after moderate exercise. She was diagnosed as having a myopathic form of VLCAD deficiency confirmed by genetic analysis (609575.0013; 609575.0014). Her first clinical symptom of the disease appeared at age 6. She had never had hypoglycemic attacks, hepatomegaly, or cardiomyopathy. In vitro functional expression studies showed that the mutant proteins were temperature-sensitive and retained residual activity at 30 degrees Celsius. Fukao et al. (2001) concluded that the temperature-sensitive mild mutations in both alleles resulted in this patient's very mild manifestations.
Andresen et al. (1999) studied 54 patients with VLCAD, several of whom had been previously reported. Twenty-five patients had the severe childhood form, 75% of whom had onset within the first 3 days of life. These patients had ... Andresen et al. (1999) studied 54 patients with VLCAD, several of whom had been previously reported. Twenty-five patients had the severe childhood form, 75% of whom had onset within the first 3 days of life. These patients had cardiomyopathy (92%), hepatomegaly (80%), hypotonia (52%), and early death (80%). Twenty-one patients had a milder childhood form with onset by 4 years of age. Clinical features in this group included cardiomyopathy (19%), hepatomegaly (62%), rhabdomyolysis or myoglobinuria (14%), hypotonia (62%), and hypoketotic hypoglycemia (76%). Eight patients had a myopathic adult form, with onset after age 13 years. All of these patients had rhabdomyolysis or myoglobinuria, whereas only 13% had cardiomyopathy and 13% had hypotonia. Genotype analysis identified 58 different ACADVL mutations among the whole group. In patients with the severe childhood form of VLCAD, the majority (71%) of mutant alleles were null, whereas in patients with the milder childhood and adult forms of VLCAD, the majority of alleles (82% and 93%, respectively) were predicted to result in some residual enzyme activity. Gregersen et al. (2001) reviewed current understanding of genotype-phenotype relationships in VLCAD, MCAD, and SCAD. They discussed both the structural implications of mutation type and the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. The realization that the effect of the monogene, such as disease-causing mutations in these 3 genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. They stated that the rapid development of mutation detection systems, such as chip technologies, made such profile analyses feasible.
In cultured fibroblasts of 2 patients with VLCAD deficiency, Aoyama et al. (1995) identified a 105-bp deletion in the ACADVL gene (609575.0001).
In 2 unrelated patients with VLCAD deficiency, Strauss et al. (1995) identified mutations in ... In cultured fibroblasts of 2 patients with VLCAD deficiency, Aoyama et al. (1995) identified a 105-bp deletion in the ACADVL gene (609575.0001). In 2 unrelated patients with VLCAD deficiency, Strauss et al. (1995) identified mutations in the ACADVL gene (609575.0002-609575.0004). Both patients had originally been diagnosed with long-chain acyl-CoA deficiency (Hale et al., 1985). Mathur et al. (1999) identified 21 different mutations in the ACADVL gene in 18 of 37 children with cardiomyopathy, nonketotic hypoglycemia and hepatic dysfunction, skeletal myopathy, or sudden death in infancy with hepatic steatosis. Sixty-seven percent of children had severe dilated or hypertrophic cardiomyopathy at presentation. In 7 patients, only 1 mutation was found despite direct sequencing of all exons. Missense, frameshift, and splice consensus sequence mutations were seen, as well as in-frame deletions. Eighty percent of these mutations were associated with cardiomyopathy. The authors concluded that infantile cardiomyopathy is the most common clinical phenotype for VLCAD deficiency and highlighted the marked allelic heterogeneity in this disorder.
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: ...
DiagnosisClinical 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 formHepatic or hypoketotic hypoglycemic formLater-onset episodic myopathic formTestingAcylcarnitine 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 unlabelled 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 TestingGene. 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 DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityACADVLSequence analysisSequence variants 2Two mutations in 47/55 and one mutation in 8/55 families with clinical disease 3ClinicalDeletion / duplication analysis 4Exonic, multiexonic, and whole-gene deletions / duplicationsUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene.2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Andresen et al [1999]4. 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 For issues to consider in interpretation of sequence analysis results, click here. In vitro functional assays have been developed to characterize mutations and understand how they cause the clinical aspects of the disease (see Molecular Genetics, Pathologic allelic variants). Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandAcylcarnitine 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, ]. 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 steatosisStudies 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/MSIf 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. Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in ACADVL.
Three clinical groups of VLCAD deficiency have been reported [Andresen et al 1999]....
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.
As a general rule, a strong genotype-phenotype correlation exists in VLCAD deficiency [Andresen et al 1999]: ...
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 p.Val243Ala mutation has usually been associated with the mild phenotype [Spiekerkoetter et al 2009].
Infantile cardiomyopathy with evidence of abnormal fatty acid oxidation may be seen in [Roe et al 2006]:...
Differential DiagnosisInfantile 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) deficiencyLong-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/ trifunctional protein deficiency. Carnitine-acylcarnitine translocase deficiencySevere 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Severe early-onset VLCADHepatic or hypoketotic hypoglycemic VLCADEpisodic myopathic VLCAD
To establish the extent of disease in an individual diagnosed with VLCAD deficiency, the following evaluations are recommended:...
ManagementEvaluations 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) concentrationMeasurement of baseline liver transaminasesCardiac echocardiographyElectrocardiogramGenetics consultationNote: In the setting of acute disease, measurement of blood glucose concentration and blood ammonia concentration may be indicated. Treatment of ManifestationsFrequently 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 ManifestationsIndividuals 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 ComplicationsAcute 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 AvoidAvoid 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 RiskIt 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 ManagementDuring 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDACADVL17p13.1Very long-chain specific acyl-CoA dehydrogenase, mitochondrialCCHMC - Human Genetics Mutation DatabaseACADVLData 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) View in own window 201475ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN, DEFICIENCY OF; ACADVLD 609575ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN; ACADVLMolecular 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 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 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]. Pathologic allelic variants. See Table 2. Hundreds of pathologic 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 pathologic 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 pathologic alleles among individuals detected by newborn screening.The remaining pathologic 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 View in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change (Alias 1)Reference SequencesNormalc.49C>Tp.Leu17PheNM_000018.2 NP_000009.1c.68G>Ap.Arg23Glnc.128G>A p.Gly43Aspc.194C>Tp.Pro65Leu 2c.1038G>Ap.Ala346AlaPathologicc.848T>Cp.Val283Ala (p.Val243Ala)c.779C>Tp.Thr260Met (p.Thr220Met)c.1226C>Tp.Thr409Met (p.Thr369Met)c.1322G>Ap.Gly441Asp (p.Gly401Asp)c.1405C>Tp.Arg469Trp (p.Arg429Trp)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 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., pathologic) gene products result from missense mutations, with reduced enzyme activity and/or reduced stability leading to lower steady state levels in mitochondria.
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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