Myopathic form of very-long chain acyl-CoA dehydrogenase deficiency: Evidence for temperature-sensitive mild mutations in both mutant alleles in a Japanese girl

In a 14-year-old Japanese girl, manifested recurrent myalgia with elevated serum creatine kinase after moderate exercise became evident, and she was d iagnosed as having a myopathic form of very-long chain acyl-CoA dehydrogena se deficiency. Her first clinical symptom of the disease was evident when s he was 6 y of age. She had never had hypoglycemic attacks, and hepatomegaly and cardiomyopathy were absent. The diagnosis was suspected on the basis o f 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 fi broblasts, 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 degreesC and 30 degreesC, respectively. Specific activity of A416T m utant protein was calculated to be one fifth that of control. In the case o f R450H mutant expression, a low residual acyl-CoA dehydrogenase activity o f 5% normal was detected at 30 degreesC although significant activity was a bsent at 37 degreesC. The R450H protein was not detected at 37 degreesC but was clearly detected at one fourth the normal amount at 30 degreesC. These results indicate that both mutations were temperature-sensitive mild mutat ions, the result being the mildest phenotype of very-long chain acyl-CoA de hydrogenase deficiency.