Home » Autism » The Awesome-ness of Dr. Brian Skotko, Part 2

The Awesome-ness of Dr. Brian Skotko, Part 2

Are you tired of reading my extremely long, drawn-out, unnecessary-detail-filled posts?  Well here are the Cliff’s Notes of this post:  Jack has a never-seen-before microduplication in part of Chromosome 4 and his autism is caused by a Serine deficiency.  Want the long, painfully detailed version of the story?  Read below:

During Jack’s appointment with Dr. Skotko at MassGeneral’s Down Syndrome Program several months ago, Dr. Skotko handed me a list of blood tests that he wanted Jack to have.  The results of that bloodwork could possibly pinpoint the origin of Jack’s autism.  Excuse me?  Are you serious?  Why doesn’t EVERYBODY know about this?!  The form contained not only the names of the tests, but also each tests’ CPT code (which insurance companies use for billing purposes).  He told me if I was interested in pursuing this, I should call my insurance company to see whether the tests were covered or not.

Was I interested in potentially discovering the cause of Jack’s autism?  Is that actually a real question?  What kind of person? . . . why would anybody? . . . who would ever? . . . YES!!!  Yes, of course I wanted to know the origin of Jack’s autism!  So I called our insurance company and discovered that they covered every test but one.  Fine, whatever.  We can pay out-of-pocket for that test.

Dr. Skotko told me that the results of the bloodwork would take approximately 3 months to come back.  Not that we were in any rush.  After all, Jack wasn’t going to “outgrow” his autism before then!

I was surprised to receive a phone call from Dr. Skotko’s program director, letting me know that the results of Jack’s autism testing had come back, and that Dr. Skotko wanted to discuss the results with us in person.  Now typically that type of phone call sends people into a panic.  ‘What?  He can’t just give me the results over the phone?  It’s cancer.  I know it’s cancer!’  But in our case, I figured that Jack’s results were just too complicated to explain over the phone.  And that turned out to be the case.

So on September 27, 2013, Dave, Jack, and I met with Dr. Skotko to receive the results of Jack’s bloodwork.  I truly hope I can explain Jack’s results in the same, simplistic way in which Dr. Skotko did.  But let’s face it, I’m long-winded.  My blog posts are proof of that!  So let me do my best to explain the extremely scientifically complex results of Jack’s autism testing:

Test #1–Fragile X Syndrome:  Normal

Test #2–microarray:  Um, wow.  Sooooo not normal.  First of all, we learned that Jack has Down syndrome.  (Whaaaaa???)  And the rest of the medical jargon is just too difficult for me to decipher, so this is EXACTLY how the report I received reads, down to the punctuation:


microarray:  An interstitial duplication at 4q25, involving 9 oligonucleutide probes and spanning 209.026 kb, was detected.

SUMMARY:  and one variant of UNCERTAIN significance was detected.  Parental testing may help determine if the copy number changes are de novo or familial variants.  Clinical correlation and genetic counseling are recommended.

Variant 2 of 2

Minimum:  arr4q25(113,573,561 – 113,782,586)x3 (209.026kb)

Maximum:  arr4q25(113,539,053 – 113,815,775)x3 (276.723 kb)


Now, let me clue you in on ONE thing I can easily explain.  Where it says “Variant 2 of 2”?  Let me just clarify that “Variant 1 of 2” was just informing us that Jack has Down syndrome.  No surprise there!

But this 2nd variant?  Let me continue to quote the report:


Associated Condition(s):  Cardiac arrhythmia, ankyrin-B related (600919); Long QT syndrome-4 (600919)

INTERPRETATION:  An interstitial duplication at 4q25, involving 9 oligonucleotide probes and spanning 209.026 kb, was detected.  The condition(s) associated with ANK2 (106410) involves an autosomal dominant loss of function mutation.  One overlapping duplication has been reported in the ISCA database as of uncertain significance.  The significance of the duplication observed in this case is unknown.  Therefore, the finding is interpreted as of UNCERTAIN significance.


Dr. Skotko did an amazing job of explaining Jack’s test results, but the entire visit was a blur to me.  Dave remembers more about Dr. Skotko’s explanation than I do, which is scary because Dave remembers NOTHING.  EVER.  Thankfully, Dr. Skotko made sure to provide us with drawings as he was explaining Jack’s results:

Skotko Drawings Circled 1

So here is a quick sketch of a few of our chromosomes.  We have two of each chromosome (two of chromosome 11, two of chromosome 22, two of chromosome 33, etc).  Each chromosome has a short arm (aka the -p- arm) and a long arm (aka the -q- arm).

Skotko Drawings Circled 2

Now, a patient with Down syndrome has THREE copies of Chromosome 21.  This is known as a “Trisomy”.

Skotko Drawings Circled 3

Now here’s what’s going on with Jack: On the long arm (q arm) of ONE OF Jack’s 4th chromosomes, there is a “microduplication” at 4q25.  However, on the long arm (q arm) of THE SECOND copy of Jack’s 4th chromosome, there is no duplication at 4q25.  As you can see in Dr. Skotko’s sketch, only having a total of ONE COPY of 4q25 (where the ANK2 gene is located) is typically associated with cardiac issues.  But if a person has THREE COPIES of 4q25 . . . well, they have no idea what the implications of this may be.  Because they’ve never seen this before.  Yep . . .


A pretty internet diagram, showing a normal chromosome on the left, and a chromosome with a duplication on the right


Here’s an internet diagram that shows roughly where Jack’s microduplication has taken place


However, here is the explanation Dr. Skotko provided in his note to Jack’s Pediatrician:

“On his chromosomal microarray, in addition to confirming the already known diagnosis of Down syndrome, Jack has an interstitial duplication at 4q25, spanning 209.026 kb.  This means that on one of the 4th chromosomes,  Jack has two times the number of genetic material at this specific location.  On his other 4th chromosome, he has the typical amount.  In total, this means that Jack has three copies of a small portion of genetic material on the long arm of chromosome 4.  This is classified as a “variant of unknown significance,” which means that based on our latest scientific advances, we do not know if this microduplication has clinical consequences.  To this extent, we have recommended that we test both of his parents for this region.  If either one of his parents were to have this same microduplication–and they are asymptomatic–then this would make it less likely to be a region of clinical significance.  If this region is de novo in Jack, then this would increase its level of clinical significance.  This duplicated area involves the ANK2 gene which can be associated with prolonged QTc syndrome; however, patients with this condition typically have a missing or mutated copy of ANK2, and not a duplicated copy.  To be extra cautious, we have ordered a screening EKG for Jack.  This was performed today and was normal.”


But here’s the next question:  Which one of us passed on this chromosomal mutation that Jack has?  Dave or me?  Well there’s another possibility, which is explained in Jack’s test results.  His test results said his chromosomal mutation could be ‘de novo’, meaning that it’s a mutation that exists solely in him, and ISN’T something he inherited from either Dave or me.  But Dave and I both had our blood drawn to test for this Chromosome 4 mutation.  I’m not sure when the results will be in, but I’ll be sure to keep you updated!

Test #3–urine organic acids:  Normal

Test #4–urine acylglycines:  Normal

Test #5–plasma acylcarnitines:  Normal

Test #6–plasma amino acids:  Ruh-roh!  Here we go again with the medical jargon:


In this plasma sample, the concentrations of serine and glycine were below the normal range.  These two amino acids are reduced (more significantly) in Serine Deficiency Syndrome (3-Phospoglycerate Dehydrogenase deficiency), an inborn error of serine biosynethesis (microcephaly, developmental delay, seizures;)  If clinically indicated consider sending a second sample to repeat the information for further interpretation.


Okay, let me summarize how AWESOME this TERRIBLE test result is!!!  THIS IS WHERE JACK’S AUTISM ORIGINATED!!!  AND IT’S POTENTIALLY TREATABLE!!!  But we’re not getting ahead of ourselves.  Dave and I don’t have delusions that all Jack needs is a pill and then he’ll start speaking in full sentences.  But the possibility that there’s something out there that could potentially increase his cognition?!  MIND-BLOWING!  Even if Dr. Skotko is able to treat Jack with some sort of supplement to replace the chemicals that his brain is lacking AND NOTHING HAPPENS . . . our son will be a part of finding a potential treatment for autism.  Not a cure, but perhaps, just perhaps, a treatment.  That’s astounding.

But as the test results said, they would like ‘to repeat the test’ if possible.  And that’s exactly what Dr. Skotko plans on doing.  How?  In two ways: First, by repeating the plasma amino acids blood test, and second, by performing an MRI, an MRA (Magnetic Resonance Angiography), and an MRS (Magnetic Resonance Spectroscopy) of Jack’s brain while he’s sedated for his previously-scheduled sedated CT-scan of his sinuses (completely unrelated to the care he’s receiving from Dr. Skotko).  In addition to those procedures, Jack will also have a repeat EKG while under sedation as well.

But we’ve hit an unsurprising bump in the road.  The dreaded Insurance Company DENIAL!  The reason for the denial?  JACK DOESN’T HAVE A BRAIN TUMOR!  (Insert eye roll)


Bottom line–does Jack need an MRS?  Yep.  Because that’s the only thing that will confirm DEFINITIVELY that his autism has resulted due to the lack of a crucial amino acid.  So Dr. Skotko took it upon himself to appeal the decision of my insurance company.  And if that appeal fails?


Our insurance is a “self-funded” plan.  Is it “non-granfathered”?  I literally don’t even know what that means.  But I recently (very, very politely) fought Dave’s company for autism coverage and LOST.  This time?  I WILL WIN.  Because I HAVE TO WIN.  The cost of this single procedure amounts to pocket change for an international company.  And if I lose this battle, we’ll wait until January and immediately max out our Flexible Spending Account.  Bottom line–the MRS is happening.  When and how?  I’m not sure yet.  But I’ll keep you updated on that as well!

But here is Dr. Skotko’s note to Jack’s Pediatrician that explains EVERYTHING:

“On his plasma amino acids, Jack’s results are very suggestive of a rare, but treatable condition, called serine deficiency.  Serine deficiency can be caused by a deficiency of three enzymes, the most common being Phosphoglycerate dehydrogenase deficiency (PHGDH).  There are only two labs in the world that do the genetic sequencing to confirm this diagnosis.  Both are CLIA certified but outside of the US–one in the Netherlands and one in Germany.  The Netherlands lab is more experienced.  Confirming this diagnosis is medically necessary and would change medical management.  To this extent, we will make arrangements to sequence the following genes from this lab:  PHGDH, PSPH, PSAT.  We have decided to first seek financial/cost information from the lab before the family decides to proceed with testing.

Serine deficiencies are also treatable, and the earlier the supplementation is begun, the better the outcomes in limited studies.  We are planning to have Jack return as soon as possible for a fasting plasma amino acid profile, which will give us another baseline.  This can be done when he is scheduled to have his brain MRI and sinus CT on October 18.  If the serine and glycine are again decreased, I will prescribe 600 mg/kg/day of L-serine in 4 divided doses.  If the repeat amino acid profile is normal, then I would start with 400 mg/kg/day of L-serine in 4 divided doses.  After supplementation is begun, I would like to repeat the fasting plasma amino acids in one month time during his return clinical visit.

Individuals with serine deficiencies can also have significant findings on their brain MRIs and brain MRS.  This will be further helpful in confirming the diagnosis.  To this extent, I will work closely with Dr. Paul Caruso in MGH radiology to arrange for a brain MRI and a brain MRS that looks at special peaks for serine and glycine.  Dr. Caruso and his team have arranged for this study to be performed on October 18 at MEEI.  His parents decided, appropriately, to reschedule his sinus CT for the same date so that all procedures can be done under sedation.  While he is under sedation, I have also arranged for the plasma amino acids and a repeat EKG to be performed.”

So to all my fellow autism parents–talk to your Geneticist about ordering the tests that I’ve mentioned.  When I find the piece of paper that lists the test names and CPT codes, I’ll update this post.  But in the meantime, please forward this to every autism parent you know.  Get your kids tested.  Perhaps there’s something out there that could help your child, even just a little!


Pink Sweatpants

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