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. 

Easter and ERs: Learning to live with Adrenal Insuffieciency

Learning to live with adrenal insufficiency is a little daunting. Just before Easter break, Gabe got into a small accident on the playground that had us rushing to the emergency room and over the holiday he caught a cold. Both events underscored for us that we don't know what we're dealing with yet and we have a lot to learn about how to handle the normal kid stuff that arises like sniffles and black eyes.

Gabriel is a rough and tumble child and coming home with bruises and scrapes from playground adventures is a regular event. Last Wednesday, he was racing at recess with another boy when, in a passing maneuver, the other boy collided him and landed on Gabe's face. It happens. I got a phone call from the office secretary to alert me that Gabe would be coming home with scrapes on his face and an eye that is bloodshot and banged up pretty good. She said that Gabe had told her that his vision was briefly a little blurry in one eye following the head-landing-upon. Well, ordinarily (pre-ALD), I would have just said "thanks for the heads up" and added another mark to the mental checklist of Gabe's battle scars, but now I know that there's adrenal insufficiency involved and I have to take his playground injuries seriously! But, how seriously? Which injuries? I told the secretary that I was on my way and rushed out the door, dialing the number for Gabe's pediatrician. With an eye injury, did this necessitate a visit to the endocrinologist? The pediatrician? The ER? None of the above?

Now, ordinarily, your adrenal glands make cortisol when you are in a stressful situation like getting sick, getting injured, interviewing for a job, bungee jumping, training for underwater demolitions, or facing a fight-or-flight scenario. In ALD, the rogue very-long-chain-fatty-acids that accumulate in the body will damage the adrenal glands, impeding the body's ability to make cortisol and other hormones. Cortisol has stuff to do with your blood sugar, salt and water balance, lowering inflammation, metabolism... The production is stimulated by the pituitary gland, which tells the adrenal glands that it's time to produce their hormones. When a situation occurs in which the body SHOULD be producing cortisol and can't, the pituitary gland starts screaming at the adrenals by releasing lots of Adrenocorticotropic Hormone (ACTH). In Gabe's case, the adrenals respond just a little, but not enough, and the pituitary keeps yelling, hoping that they'll get the adrenal's attention. Gabe's ACTH has been extremely high lately, anyway, without injury or illness.

I got up with the pediatric nurse and explained the situation: that Gabe has adrenal insufficiency secondary to Adrenoleukodystrophy and had gotten an eye injury when another boy fell on his head on the playground. I hadn't seen it yet, but the school said it was bruised, bloodshot, and blurry. She said that I should give him a stress dose of hydrocortisone and go ahead and bring him to the ER since, with the adrenal issues and it involving his eye, they'd probably want to look him over. When I picked him up, I saw that the injury wasn't nearly as bad as it had sounded on the phone. I gave him twice his afternoon dose (10 mg) and brought him to the ER. They saw him quickly, deemed him okay, and confirmed the stress dose of double his hydrocortisone. The doctor we saw said that he probably wouldn't need the evening dose to be doubled, but it couldn't hurt, so we gave him a double dose in the evening. I was a little embarrassed to be in the ER over such a small injury, but we're new to this whole adrenal thing.

Two days after Gabe's injury, he woke up feeling bad. He had a terrible headache, felt nauseous  and had a
low temperature. I gave him some ibuprofen, but it didn't seem to help a bit. Two hours later, he was still lying on the couch moaning about his head and feeling sick. It took some time to get up with an Endocrinologist, even using the on-call number, and I was starting to freak out a little by the time I finally did.  She said to triple his hydrocortisone dose and to give him the 50mg shot if he threw up. It was surprising to see how fast he bounced back. Pretty soon, he was up playing video games, then he was feeling back to himself and we went for a walk. The following day, though, he was feeling sick again and had developed a cough. By the middle of the day on Easter, he was running a fever of 102.6. We were all on pins and needles, unsure if this was a true illness, if it was (at least in part) an adrenal crisis, if we were doing things right, if he needed to go back into the ER... I'm just glad that he didn't start throwing up! On Tuesday, just 4 days after it started, he was feeling a deal better and the cough had almost disappeared, so we lowered his hydrocortisone to twice the usual amount. Wednesday he seemed back to normal, so we returned to the regular dose. He's back on the usual dose now and seems okay, but we're still a little nervous. I guess that we'll get the hang of this eventually, but right now we're still learning the stress to hydrocortisone ratio and the appropriate scoring of emergencies.

To conclude on a high note, though, we did get spectacular news Tuesday! It would appear that our twelve year old daughter, Cai, is NOT a carrier for ALD! The very-long-chain-fatty-acid blood test has a 85% accuracy in being able to tell if a female is a carrier, so there's still a little wiggle room for error, but there is a really great chance (an 85% chance) that she is ALD gene free! That would mean that she also has a really great chance of being Gabe's donor should he need a bone marrow transplant.

Our family had a wonderful Easter and a fantastic Holy Week. We dyed eggs, were surprised by a live, fun Stations of the Cross event at church on Holy Thursday (we were expecting just regular subdued stations, not the traditional Via Crucis with actors and guitar playing), celebrated a beautiful Easter vigil service by candle light in which the whole church seemed filled with twinkling stars, watched The Ten Commandments like we do every year (no finer example of 50s cinema will one find than this!), had an Easter egg hunt, and of course, ate far too much candy. Many years ago I started an Easter Pinata tradition. I don't know why, it just seemed like a fun thing to do at the time, and we continued the tradition every year since. This year they had a lot of fun trying to bust it open with a golf club. Cai was the winner; she knocked that poor pinata right in half.  We hope that, whatever you celebrate you had a great holiday, too!