Dimethylglycine Dehydrogenase Deficiency via the DMGDH Gene

DMGDH deficiency is caused by a defect in the mitochondrial enzyme dimethylglycine dehydrogenase. To date, only a single patient with a defect in the DMGDH enzyme has been described. This patient presented with markedly increased concentrations of dimethylglycine in his urine and serum, a fishlike body odor that increased in intensity with physiological stressors or activity, and chronic muscle fatigue accompanied by increased serum creatine kinase levels (Moolenaar et al. 1999; Binzak et al. 2001). He was found to have normal growth and intelligence, and all other metabolic testing was normal (Binzak et al. 2001). Onset of symptoms occurred at 5 years of age, and the patient was still symptomatic when diagnosed in his late 30s.

The DMGDH enzyme is a folate binding protein, and for this reason, patients with folate or cobalamin disorders are sometimes found to have increased dimethylglycine levels in the urine or serum. In contrast, the described DMGDH deficient patient had normal biochemical test results for folate and cobalamin disorders (Moolenaar et al. 1999; Binzak et al. 2001).

The DMGDH enzyme is encoded by the DMGDH gene, which is located on chromosome 5 (at 5q14.1). Thus far, DMGDH deficiency appears to be inherited in an autosomal recessive manner (Binzak et al. 2001). The one reported patient with a deficiency in the DMGDH gene was found to have a missense substitution, His109Arg, in the homozygous state (Moolenaar et al. 1999; Binzak et al. 2001; Human Gene Mutation Database).

The dimethylglycine dehydrogenase (DMGDH) enzyme is involved in the catabolism of choline within the mitochondria. This enzyme is responsible for the transfer of one methyl group from dimethylglycine to form the modified amino acid sarcosine, which is one step in the choline catabolic pathway (Moolenaar et al. 1999; Binzak et al. 2001).

At this time, the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature. Analytical sensitivity may be high as the only reported causative variant is detectable by sequencing.

This test provides full coverage of all coding exons of the DMGDH gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).