DNA results: Gabe Gets his Mutant Certificate!

When a doctor says he has something to discuss and is willing to meet you outside of normal clinic hours, you know that a) something is up and b) you have a really good doctor. So it was with great appreciation and no small dose of trepidation that I anticipated this morning’s meeting.  Exhausted from a night of working the graveyard shift, I stumbled into their office building, still dressed in the scrubs of a competing hospital.  Gabe and I were escorted to a conference room filled with toys and the drawings of young bone marrow transplant survivors.   The colorful pictures were supposed to be inspiring, but seeing them made me want to cry. For all their celebratory happiness, they were draped with the shadows of all the missing drawings of children who never got the chance to scribble rainbows thanking the team for saving their lives. If Gabe noticed the artwork, he didn’t mention it or stop to look. Maybe to children, drawings decorating the walls are so common that they’re like silverware in the kitchen. Gabe got to work checking out everything in the room for its play-with potential, but deemed most stuff “too babyish” for him. He eventually settled on a calculator.

Dr. T and Nurse M are very personable people. They are both kind and generate a sense of ease and familiarity. Nevertheless, I could tell by the stack of papers that they carried and the fact that they seem to have made an exception to meet with me during odd hours that this wasn’t just a friendly morning meeting to touch base.

First, we discussed Gabe’s latest ACTH levels. They are even higher than the last labs and, once again, they are off the charts (over 2000). This means that his pituitary is not responding to the oral meds. His endocrinologists have put him on another week of decadron, this time at 1mg  instead of .5mg. Dr. T said that this is a strong steroid, so they should see some improvement by the next labs in May.

They showed me a print-out of Gabe’s results from John Hopkins DNA Diagnostic Laboratory. It turns out that Gabe has a never-before-identified mutation to his ABCD1 gene.  There are many different mutations on the ABCD1 gene, hundreds in fact, that cause ALD and Gabriel’s mutation is a new one to their database. Specifically, it is a mutation that changed from what was supposed to be a simple amino acid called glycine into a positively charged amino acid called arginine. This sounds small, but Dr. T says that it’s actually a significant mutation and that it is predicted to, eventually, cause cerebral involvement. Here is the interpretation from the data sheet:

 c.1534G>C (p.Gly512Arg): Not a previously reported ABCD1 gene mutation or polymorphism to our knowledge. Two different mutations affecting the nucleotide at this position (c.1534G>T, p.Gly512Cys; c.1534G>A, p.GLY512Ser) have been previously reported in patients with an ABCD1-related disorder. Two bioinformatic tools were queried and both predict that c.1534G>C is probably damaging. The glycine residue at this position 512 is completely evolutionarily conserved across multiple species. If the patient meets clinical or biochemical diagnostic criteria for ABCD1-replated disorder, c1534G>C is likely the molecular cause of disease.

If you think about it, this DNA analysis form is kind of like a mutant certificate. Like the first page in an entrance application to Xavier's School for Gifted Young Mutants. I wish it were that awesome, anyway.

The prediction is that this mutation, being what it is, will cause a lot of damage. There is no guarantee, however, and even major mutations can have mild expressions – it’s just the luck of the genetic lottery. But, because of this, the doctors want to get prepared. They think they will do Gabe’s next MRI the first week of June when the kids get out of school. The would like, by then, to have everything lined up to do a transplant immediately if they see anything on the MRI. They said that the transplant is not worth the risk without seeing a need for it on MRI, but that as soon as they do see changes, they want to be able to move right away. What they are doing, then, to prepare is beginning by verifying that Gabe’s sister, Cai, is a bone marrow match and not a carrier.  Her very-long-chain-fatty-acid test was in the middle of the normal range with an 80% accuracy rate. Now that they know what mutation they are looking for, they will verify her results with a DNA test. The low-resolution HLA typing looks like she is a perfect match, but they have to do a high-resolution test to be sure that all of the numbers line up.

Dr. T stressed the importance of getting myself and other members of my family tested. It is possible but unlikely that Gabe is the index mutation in our family. The occurrence rate of the gene for ALD is about 1:17,000 and the occurrence among this small number of being the first member of a family with the mutation is only about 3%. Other family members with the gene will need to be identified to be sure that treatments are conducted in a timely manner and so that genetic counseling can be given to ladies of childbearing age and inclination. Early detection is the key to survival among boys and proper identification in female carriers is important for managing the symptoms of the female carrier version (AMN).  It’s more likely that Gabe comes from a long line of mutants that have been hither-to unidentified since Gabe is the first boy to show symptoms during childhood. I wonder when our powers will surface.  Do you get a letter from Professor X the same way Harry Potter got a letter to Hogwarts? Will Patrick Stewart show up to whisk Gabe off to the academy? That sounds a lot more cool than a bone marrow transplant.