Myopathic Form of Very-Long Chain Acyl-CoA Dehydrogenase Deficiency: Evidence for Temperature-Sensitive Mild Mutations in Both Mutant Alleles in a Japanese Girl

Abstract

In a 14-year-old Japanese girl, manifested recurrent myalgia with elevated serum creatine kinase after moderate exercise became evident, and she was diagnosed as having a myopathic form of very-long chain acyl-CoA dehydrogenase deficiency. Her first clinical symptom of the disease was evident when she was 6 y of age. She had never had hypoglycemic attacks, and hepatomegaly and cardiomyopathy were absent. The diagnosis was suspected on the basis of the urinary organic acid profile after a 36-h fast, long-chain fatty acid-loading test, and the blood acylcarnitine profile. Acyl-CoA dehydrogenase activity with palmitoyl-CoA as a substrate was severely decreased in her fibroblasts, and the amount of very-long chain acyl-CoA dehydrogenase protein was reduced. She was a compound heterozygote of A416T from her father and R450H from her mother. Transient expression of mutant A416T cDNA retained a significant residual acyl-CoA dehydrogenase activity of 10% and 20% normal at 37°C and 30°C, respectively. Specific activity of A416T mutant protein was calculated to be one fifth that of control. In the case of R450H mutant expression, a low residual acyl-CoA dehydrogenase activity of 5% normal was detected at 30°C although significant activity was absent at 37°C. The R450H protein was not detected at 37°C but was clearly detected at one fourth the normal amount at 30°C. These results indicate that both mutations were temperature-sensitive mild mutations, the result being the mildest phenotype of very-long chain acylCoA dehydrogenase deficiency. VLCAD(EC 1.3.99.13; HUGO symbol, ACADVL) belongs to the ␤-oxidation system of long-chain fatty acids together with mitochondrial enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase trifunctional protein (1, 2).The clinical phenotype of VLCAD deficiency (MIM# 201475) was first divided into two different forms (3); a severe presentation characterized by early onset of symptoms, with hypertrophic cardiomyopathy and a high incidence of death, and a milder form with a late onset with Reye-like disease, hypoketotic hypoglycemia, no cardiac involvement, and a more favorable outcome. Later occurrences in adolescents and adults have been reported, with the absence of hypoglycemia and cardiomyopathy but with episodes of rhabdomyolysis and myoglobinuria, usually triggered by exercise or fasting (4 -7). Hence VLCAD deficiency can be separated into three clinical phenotypes (8).Gene mutations in VLCAD deficiency have been reported, with a wide spectrum (8 -14). Andresen et al. (8) suggested a clear correlation of genotype with disease phenotype in VLCAD deficiency, from data on 58 independent mutations in 55 unrelated patients. They reported that most patients with the severe childhood form had two null mutations and that most

MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency

“…Later-onset disease is usually characterized by myopathic symptoms, and onset is in adolescence or adulthood. 5,25 848T…”

A Heterozygous Missense Mutation in Adolescent-Onset Very Long-Chain Acyl-CoA Dehydrogenase Deficiency with Exercise-Induced Rhabdomyolysis

“…More than 100 mutations such as missense, small deletion, and abnormal splicing due to insertions of IVS have been identified in ACADVL, and mutations are distributed all over the gene (Gregersen et al 2008). Near the mutation site of the present case, two pathogenic substitutions; p.A416T (c.1246G>A) and p.T409M (c.1226C>T), have been reported (Fukao et al 2001;Isackson et al 2013). Two single nucleotide variations resulting in an amino-acid change before position 414 have also been identified (rs201606472; c.1237A>G, p.I413V and rs143172658; c.1239A>G, p.I413M).…”

Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches

“…In contrast, the genotype D405H/R450H most likely associates two mild mutations. Indeed, previous studies using transient expression in SV-40 fibroblasts demonstrated that R450H is a mild temperature-sensitive mutation [20]. Furthermore, modeling of D405H showed that the conserved Asp405 is located on the surface of the molecule and that substitution to a hydrophilic His would probably have mild consequences on protein structure and stability.…”