DWQA QuestionsCategory: QuestionsGA2 Gene Set
Lori asked 1 year ago
What are the specific genes related to a late onset GA2 diagnosis today beyond ETFDH, ETFA and ETFB? I see on your site that there were at one time as many as seven genes implicated.
Are there any other genes that could or should be evaluated in the context of elevated urine 2OH-Glutaric Acid and 2-OXO-Glutaric Acid accompanied by elevated blood lactic acid and ammonia with a necessity for carbohydrate consumption every 2-3 hours 24 hours a day and seizures resulting from high fat meals?
Would you anticipate any synergistic impact from sequence heterozygosity with mutations in either OGDH or IDH1?
Keith McIntire
replied 1 year ago

ETFA, ETFB, and ETFDH are the genes originally identified as causing GA2. The encode the proteins that directly shuttle the energy from the acyl-CoA dehydrogenases involved in fatty acid oxidation and branched chain amino acid metabolism to the respiratory chain. The acyl-CoA dehydrogenases require a modified version of the vitamin riboflavin (B2) called FAD to work, and there are now a number of genes involved in importing riboflavin and making the FAD. Defects in any of these can cause a GA2 type picture though sometimes the clinical picture is a bit more complicated. That list of genes includes SLC52A1, SLC52A2, SLC52A3, and FADS (also known as FLAD1). Keep in mind that anything that causes severe mitochondrial energy dysfunction such as disorders of the electron transport chain and even severe infections or shock, can lead to a transient picture of GA2. So our usual approach to diagnosing GA2 once there is a suspicion based on biochemical testing, is to either start with a targeted panel that includes all these genes and go to whole exome sequencing if no answer is found, or just to go straight to the latter depending on the clinical symptoms. The 2-hydroxygutaric acidemias(2HGA) are a completely different group of disorders and won’t be confused with GA2 because of biochemical testing. They are ultimately diagnosed by DNA sequencing. Anyone with either set of findings should be evaluated by a metabolic geneticist. There has been no research on synergism in the 2-HGA genes. I hope this helps. Jerry Vockley