Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency

Dimethylglycine dehydrogenase (DMGDH) (E.C. number 1.5.99.2) is a mitochond rial matrix enzyme involved in the metabolism of choline, converting dimeth ylglycine to sarcosine. Sarcosine is then transformed to glycine by sarcosi ne dehydrogenase (E.C. number 1.5.99.1). Both enzymes use flavin adenine di nucleotide and folate in their reaction mechanisms. We have identified a 38 -year-old man who has a lifelong condition of fishlike body odor and chroni c muscle fatigue, accompanied by elevated levels of the muscle form of crea tine kinase in serum. Biochemical analysis of the patient's serum and urine , using H-1-nuclear magnetic resonance NMR spectroscopy, revealed that his levels of dimethylglycine were much higher than control values. The cDNA an d the genomic DNA for human DMGDH (hDMGDH) were then cloned, and a homozygo us A-->G substitution (326 A-->G) was identified in both the cDNA and genom ic DNA of the patient. This mutation changes a His to an Arg (H109R). Expre ssion analysis of the mutant cDNA indicates that this mutation inactivates the enzyme. We therefore confirm that the patient described here represents the first reported case of a new inborn error of metabolism, DMGDH deficie ncy.