Clinical and molecular studies on in born errors of ketone body metabolism

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SCOT deficient patients with "mild" mutation : We analyzed 3 Japanese families with SCOT deficient patients at the clinical and molecular level. We disclosed that SCOT deficient patients with "mild" mutations do not show a pathognomonic permanent ketosis. This indicates that we can not exclude SCOT deficiency if patients do not have permanent ketosis (Submitted).Characterization of mutations at the initiator methionine codon in T2 deficiency : We identified an initiator codon mutation, c.2T>C, heterozygously in GK30 (The other mutation was 149delC). We made expression vectors for 9 possible missense mutations at the initiator codon and analyzed the efficiency of translation initiation at the mutant initiator codons. Although the efficiencies were variable among the mutations, all the mutant initiator methionine codons were functioned as the initiator codon. Hence we concluded that initiator codon mutations result in "mild" mutations in T2 deficiency (2003).Characterization of T2 defici … More ent patients with "mild" mutations : We analyzedphenotype/genotype correlation in 5 Japanese T2 deficient patients and revealed characters for T2 deficient patients with "mild" mutations. We found no significant differences in the frequency and severity of ketoacidotic crises between patients "mild" and "severe" mutations. However, during non-episodic condition, abnormalities in urinary organic acid and blood acylcarnitine profiles was subtle in patients with "mild" mutations and they, can be missed as normal if these analyses are performed during non-episodic condition (2003). We also raised a possibility that patients with "mild" mutations were mis-diagnosed as normal by a coupled assay with tyglyl-CoA (submitted)SCOT, 3HBD knockout mice : We cloned genomic fragments necessary for construction of knockout constracts and are still making constructs.Establishment of enzyme assay for 2-methyl-3-hydroxybutyrate dehydrogenase deficiency and its clinical analysis : We established enzyme assay method for this enzyme using fibroblasts and lymphocytes. We did not find this enzyme defect in cell lines which were previously ruled out T2 deficiency. Less