Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a long-chain fatty acid oxidation disorder that manifests as either a severe phenotype associated with cardiomyopathy, a hypoglycemic phenotype, or a myopathic phenotype. As the hypoglycemic phenotype can cause sudden infant death, VLCAD deficiency is included in newborn screening (NBS) panels in many countries. The tetradecenoylcarnitine (C14:1) level in dried blood specimens is commonly used as a primary marker for VLCAD deficiency in NBS panels. Its ratio to acetylcarnitine (C2) and various other acylcarnitines is used as secondary markers. In Japan, tandem mass spectrometry-based NBS, initially launched as a pilot study in 1997, was introduced to the nationwide NBS program in 2013. In the present study, we evaluated levels of acylcarnitine with various chain lengths (C18 to C2), free carnitine, and their ratios in 175 infants who tested positive for VLCAD deficiency with C14:1 and C14:1/C2 ratios. Our analyses indicated that the ratios of C14:1 to medium-chain acylcarnitines (C10, C8, and C6) were the most effective markers in reducing false-positive rates. Their use with appropriate cutoffs is expected to improve NBS performance for VLCAD deficiency.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive long-chain fatty acid oxidation disorder caused by mutations in the ACADVL gene. The myopathic form presents with exercise intolerance, exercise-related rhabdomyolysis, and muscle pain, usually starting during adolescence or adulthood. We report on a 17-year-old boy who has presented with exercise-induced muscle pain and fatigue since childhood. In recent clinical history, episodes of exercise-related severe hyperCKemia and myoglobinuria were reported. Electromyography was normal, and a muscle biopsy showed only \"moth-eaten\" fibers, and a mild increase in lipid storage in muscle fibers. NGS analysis displayed the already known heterozygote c.1769G>A variant and the unreported heterozygote c.523G>C change in ACADVL both having disease-causing predictions. Plasma acylcarnitine profiles revealed high long-chain acylcarnitine species levels, especially C14:1. Clinical, histopathological, biochemical, and genetic tests supported the diagnosis of VLCAD deficiency. Our report of a novel pathogenic missense variant in ACADVL expands the allelic heterogeneity of the disease. Since dietary treatment is the only therapy available for treating VLCAD deficiency and it is more useful the earlier it is started, prompt diagnosis is essential in order to minimize muscle damage and slow the disease progression.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a relatively common inborn error of metabolism, but due to difficulty in accurately predicting affected status through newborn screening, molecular confirmation of the causative variants by sequencing of the ACADVL gene is necessary. Although the ACMG/AMP guidelines have helped standardize variant classification, ACADVL variant classification remains disparate due to a phenotype that can be nonspecific, the possibility of variants that produce late-onset disease, and relatively high carrier frequency, amongst other challenges. Therefore, an ACADVL-specific variant curation expert panel (VCEP) was created to facilitate the specification of the ACMG/AMP guidelines for VLCADD. We expect these guidelines to help streamline, increase concordance, and expedite the classification of ACADVL variants.

BACKGROUND: Very long-chain acyl-coenzyme-A dehydrogenase deficiency is a rare, severe life-threatening metabolic disorder of mitochondrial fatty acid oxidation, caused by mutations in ACADVL gene. Here we present a genetically confirmed case of a South Asian baby girl with severe, early-onset form of very long-chain acyl-coenzyme-A dehydrogenase deficiency due to a novel mutation in ACADVL gene.
METHODS: Index case was the second baby girl of second-degree consanguineous South Asian parents. She had an uncomplicated antenatal period and was born by spontaneous vaginal delivery at term with a birth weight of 2910 g. She had been noted to have fair skin complexion, hypotonia, and 3 cm firm hepatomegaly. Since birth, the baby developed grunting, poor feeding, and recurrent episodes of symptomatic hypoglycemia and convulsions with multiple semiology. Her septic screening and urine ketone bodies were negative. The baby had high anion gap metabolic acidosis and elevated transaminases and serum creatine phosphokinase levels. Echocardiogram at 4 months revealed bilateral ventricular hypertrophy. Acylcarnitine profile revealed elevated concentrations of tetradecanoylcarnitine (C14), tetradecanoylcarnitine C14:1, and C14:1/C16. Unfortunately, the baby died due to intercurrent respiratory illness at 4 months of age. Sequence analysis of ACADVL gene in perimortem blood sample revealed homozygous frame shift novel variant NM_001270447.1, c.711_712del p.(Phe237Leufs*38), which confirmed the diagnosis of very long-chain acyl-coenzyme-A dehydrogenase deficiency.
CONCLUSIONS: This case demonstrates the importance of early diagnosis and management of very long-chain acyl-coenzyme-A dehydrogenase deficiency in improving the outcome of the patients. Implementation of newborn screening using tandem mass spectrometry in Sri Lanka will be beneficial to reduce the morbidity and mortality of treatable disorders of inborn errors.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a genetic disorder of fatty acid beta oxidation that is caused by a defect in ACADVL, which encodes VLCAD. The clinical presentation of VLCAD deficiency is heterogeneous, and either a delayed diagnosis or a misdiagnosis may sometimes occur. We herein describe a difficult-to-diagnose case of the muscle form of adult-onset VLCAD deficiency with compound heterozygous ACADVL mutations including c.790A>G (p.K264E) and c.1246G>A (p.A416T).

Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD deficiency), a rare autosomal recessive disorder, is characterized by hypoketotic hypoglycemia, cardiomyopathy, liver damage, and myopathy. VLCAD deficiency is caused by defects of ACADVL gene, which encodes VLCAD protein. The aim of this study was to determine the clinical, biochemical, prognosis and mutation spectrum of patients with VLCAD deficiency in mainland China. A total of Six families visited us, four patients (2 boys and 2 girls) were admitted in hospital due to liver dysfunction, hypoglycemia, and positive newborn screen result. The parents of the other two patients (2 girls) visited us for genetic consultation after their children\'s death. All the six patients had elevated level of serum tetradecenoylcarnitine (C14:1-carnitine), four of them showed decreased free carnitine (C0) level, and three had dicarboxylic aciduria. Eight types of mutations of the ACADVL gene were detected, three of them are novel, including c.563G > A (p.G188D) c.1387G > A (p.G463R) and c.1582_1586del (p.L529Sfs*31). The p.R450H mutation accounts for 9/52 alleles (5/40 in previous study of 20 unrelated patients, and 4/12 in this study) of genetically diagnosed Chinese VLCAD deficiency cases. The four alive patients (Patient 1-4) responded well to diet prevention and drug therapy with stable hepatic dysfunction condition. In conclusion, we describe three novel mutations of the ACADVL gene among six unrelated families with VLCAD deficiency. Moreover, we suggest that the p.R450H may be a potential hotspot mutation in the Chinese population.

BACKGROUND: Very long chain acyl CoA dehydrogenase (VLCAD) deficiency (OMIM#201475) is an autosomal recessive disorder of fatty acid beta oxidation caused by defect in the ACADVL. The aim of this study was to analyze the clinical, biochemical, and molecular features of VLCAD deficiency in Saudi Arabia, including the treatment and outcome.
METHODS: We carried out a retrospective chart review analysis of 37 VLCAD deficiency patients from two tertiary centers in Saudi Arabia, over a 14-year period (2002-2016). Twenty-three patients were managed at King Abdul-Aziz Medical City and fourteen patients at King Fahad Medical City.
RESULTS: Severe early onset VLCAD deficiency is the most frequent phenotype in our patients, caused by four different mutations in ACADVL; 31 patients (83.7%) had a homozygous nonsense mutation in exon 2 of ACADVL c.65C>A;p. Ser22X. Twenty-three patients died before the age of 2 years, despite early detection by newborn screening and implementation of treatment, including supplementation with medium chain triglycerides.
CONCLUSIONS: This study reports the clinical, biochemical, molecular findings, treatment, and outcome of patients with VLCAD deficiency over the last 14 years. We identified the most common variant and one new variant in ACADVL. Despite early diagnosis and treatment, the outcome of VLCAD deficiency in this Saudi Arabian population remains poor. Preventive measures, such as prenatal diagnosis, could be implemented.

Fatty acid oxidation (FAO) defects often present with multi-system involvement, including several life-threatening cardiac manifestations, such as cardiomyopathy, pericardial effusion and arrhythmias. We report herein a fatal case of cardiac dysfunction and rapid-onset tamponade following an acute illness in a neonate with molecularly proven very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (harboring the known del799_802 mutation), requiring 15 days of extracorporeal membrane oxygenation (ECMO) treatment. As data regarding the use of ECMO in FAO defects in general, and VLCAD in particular, are scarce, we review the literature and discuss insights from in vitro models and several successful reported cases.

Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD; OMIM#201475) is a rare metabolic disorder of mitochondrial fatty acid oxidation. VLCADD includes three clinical forms that are grouped based on disease severity. Here, we present two unrelated patients suspected of having VLCADD based on a newborn screening test. One patient was diagnosed in the neonatal period and, to date, has not shown any symptoms or signs associated with VLCADD; in contrast, diagnosis was delayed in the other patient after events of hypoketotic hypoglycemia and steatohepatitis. Repeated biochemical analyses and a liver biopsy implied VLCADD, and direct sequencing analysis led to the discovery of three novel mutations, including an identical missense variant (p.Ser207Pro) on ACADVL. Our patients were the first cases of the milder form of VLCADD, and the identical mutation detected might represent a founder mutation in the Korean population and be associated with the milder phenotype of VLCADD.

Very long chain acyl-coA dehydrogenase deficiency (VLCADD) is an autosomal recessive inborn error of fatty acid oxidation detected by newborn screening (NBS). Follow-up molecular analyses are often required to clarify VLCADD-suggestive NBS results, but to date the outcome of these studies are not well described for the general screen-positive population. In the following study, we report the molecular findings for 693 unrelated patients that sequentially received Sanger sequence analysis of ACADVL as a result of a positive NBS for VLCADD. Highlighting the variable molecular underpinnings of this disorder, we identified 94 different pathogenic ACADVL variants (40 novel), as well as 134 variants of unknown clinical significance (VUSs). Evidence for the pathogenicity of a subset of recurrent VUSs was provided using multiple in silico analyses. Surprisingly, the most frequent finding in our cohort was carrier status, 57% all individuals had a single pathogenic variant or VUS. This result was further supported by follow-up array and/or acylcarnitine analysis that failed to provide evidence of a second pathogenic allele. Notably, exon-targeted array analysis of 131 individuals screen positive for VLCADD failed to identify copy number changes in ACADVL thus suggesting this test has a low yield in the setting of NBS follow-up. While no genotype was common, the c.848T>C (p.V283A) pathogenic variant was clearly the most frequent; at least one copy was found in ~10% of all individuals with a positive NBS. Clinical and biochemical data for seven unrelated patients homozygous for the p.V283A allele suggests that it results in a mild phenotype that responds well to standard treatment, but hypoglycemia can occur. Collectively, our data illustrate the molecular heterogeneity of VLCADD and provide novel insight into the outcomes of NBS for this disorder.