DWQA QuestionsCategory: Questionssynergistic heterozygosity
Michael Brady asked 4 years ago
Hello,
What is your current opinion of synergistic heterozygosity in FAO and mitochondrial genes eliciting myopathic symptoms? Specifically, would you expect deleterious interactions among CPT2, TK2, and/or possibly POMGNT1? If so, would you anticipate that triheptanoin or other recent FAO treatments may be helpful in this circumstance?
If context details help: I am in my 50’s with exercise intolerance symptoms starting in my teens, and have had slow but steady progression of reduced exercise capability, increasing myalgia, fatigue, spasms (and some recent spasticity), and mild weakness and tremors (no rhabdomyolysis). Elevated citrate synthase in muscle biopsy, 20.21 micromol/min/gm vs ref range 7.33 – 12.33 (subsarcolemmal accumulations of mitochondria observed); total CPT borderline low at 49.95 micromol/min/gm vs ref range > 46.6 (50% of median); CPT/CS ratio of 2.47 in range of possible manifesting CPT2 deficiency carrier/secondary CPT2 deficiency; (C16 + C18:1)/C2 = 0.198; CPT2 heterozygous for c.341-16T>C (unknown significance) (V368I and M647V polymorphisms); TK2 heterozygous pathogenic mutation (c.416 C>T); POMGNT1 heterozygous for c.1502 T>C (candidate pathogenic mutation).
Thank you.
Keith McIntire
replied 4 years ago

Mr. Brady, since I originated the concept of synergistic heterozygosity I of course am a believer in the right circumstances. Hundreds of genes for as many proteins need to interact for normal energy metabolism to occur, and in my original manuscript on this topic, I show some statistics that demonstrate that combinations of heterozygous mutations in multiple genes in a related pathway will be more frequently than traditional homozygous mutations in one gene. That said, it’s very difficult to move from this concept to proof. Your CPT2 gene variants may be sufficient to explain your symptoms, but may be a risk factor that is brought to surface by mild dysfunction in the other genes you reference. Sorting this out will require another lifetime of research. From a practical standpoint, it is more important to address your symptoms from a functional standpoint and identify life style or medication options that will help you optimize your function. This will require an ongoing conversation with your physicians. I’m sorry I can’t be more specific in my answer. Dr. Vockley