CNN: New Genetic Disorder Discovered

Kids who don't cry: New genetic disorder discovered

By Jacque Wilson, CNN

updated 2:53 PM EDT, Thu March 20, 2014

Grace Wilsey was born with NGLY1 deficiency, which is caused by two mutations in the NGLY1 gene.

(CNN) -- What do you do when your baby lies limp in your arms, staring blankly into the distance while never crying?

What do you do when tests show signs of liver damage and your baby's seizures won't stop, but doctors can't tell you what's wrong or how to fix it?

Thanks to the Human Genome Project, which was completed in 2003, identifying new genetic mutations has gotten easier and cheaper. But geneticists often struggle to find patients who share these rare DNA quirks. Studying multiple patients with the same gene mutations and similar symptoms is crucial to identifying a new genetic disorder.

That's why a paper published Thursday in the journal Genetics in Medicine is so remarkable.

The paper identifies NGLY1 deficiency as an inherited genetic disorder, caused by mutations in the NGLY1 gene. The researchers have confirmed eight patients with these mutations who share several symptoms, including developmental delays, abnormal tear production and liver disease.

And they credit an "Internet blog" with bringing the patients and scientists together.

Read the FULL STORY at CNN.com

Back to "normal".

Watching the horses at Wheeler Farm.
Victoria smiles at her brother.	Bertrand laughs at his sister.

This afternoon, Beli and I took the kids to Wheeler Farm. Both kids love animals - the louder, the smellier, the bigger, the better.  :)

Upon getting home, we got some good news about Bertrand's labs.  His CBC and CMP values have basically normalized.  His sodium is still a shade low at 133 but everything else looks great for Bertrand.  I am so relieved to see his ALT at 55 and AST at 56!  Heck, even his platelets high at 424.  This means his liver and bone marrow are functioning well.  

In other news, Bertrand's tonsillectomy evaluation was set for later this month, and I am working to get his liver biopsy sample to the folks at Sanford-Burnham. 

We go to the zoo tomorrow and titi Aury comes out this weekend!  The summer fun has begun.  :)

DIAGNOSIS!!! N-Glycanase Deficiency

Our family at Duke University - happy with the study results!

On May 3, 2012, after four long years of searching, Bertrand finally received a diagnosis!

The result.  We could undertake PGD IVF if desired.

Last week, we went to Duke University (as several readers guessed) to receive the official results of a study entitled "Genomic Study of Developmental Delay and Congenital Anomalies of Unknown Etiology" that our family joined back in July 2010.

Using next generation sequencing, the fabulous researchers at Duke University discovered that Bertrand inherited 2 distinct mutations in the NGLY1 gene: a frameshift in exon 12 from me and a nonsense mutation in exon 8 from Matthew.  NGLY1 encodes N-glycanase 1, which is the enzyme involved with the degradation of misfolded N-linked glycoproteins.

Bertrand, Cristina, Matthew and control NGLY1 expression.

In Matthew and my case, we each have a normal copy of NGLY1 to compensate for our mutated copies.  We each produce about half the N-glycanase as a normal person.  However, with both mutations, Bertrand produces basically none.  This leads to the build-up of misfolded glycoproteins in his cells.  This is why Bertrand's phenotype is consistent with a congenital disorder of glycosylation and there are similarities with other storage disorders.

(It's worth noting that testing revealed Victoria inherited both of our normal NGLY1 copies.)


Bertrand is the first documented case of an NGLY1 disorder.  Efforts are currently underway to confirm a second case of N-glycanase deficiency and establish causality.  You read that right: within 2 weeks we may know for certain if another child has the same kind of disorder as Bertrand!  And, after that, other similar but undiagnosed children may be tested for errors in NGLY1 as well.

We finally have an answer.

Something to write in on forms.  Something to easily say when people ask about Bertrand.

And, as more NGLY1 children are found, we will no longer be alone.

Inflammatory Bowel?

Bertrand looking enthusiastic.

"You poke my belly and now you want to do WHAT to my butt?!"

At Bertrand's GI appointment today, the doctor told us to stop his medication ursodiol/actigall because his liver enzymes have normalized. (Bertrand was on 180mg 3 times a day for over a year and a half.) At the follow-up appointment in 6 months, if Bertrand's liver enzymes have risen again, he will reinstate the ursodiol. But for now, that's one less medication! Yippee!

Also, Bertrand's faecal calprotectin test came back elevated. This usually calls for a colonoscopy. But, because this test has some false positives and the colonoscopy is a sedated procedure, the doctor ordered a repeat of the test, which is just a fecal sample. The reason this test was ordered in the first place was to check for inflammatory bowel (not to be confused with irritable bowel). The bowel is where many vitamins are absorbed, and chronic inflammation interferes with vitamin absorption. Causes could be anything from Crohn's disease (not likely) to metabolic disorder (duh), so now that's on the table. Fingers crossed for a normal result!

P.S. - Bertrand's weight is much better but the doctor still wants him to lose more. :(

Lab Results

Blood drawn on December 30, 2011

Medication Levels:

VPA 93.3 (50-125)

Lamotrigine 9.9 (3.0-14.0)

Complete Blood Count:

MCV 89 (75-87) *High

MCH 30.4 (24-30) *High

Platelets 130 (150-400) *Low

Comprehensive Metabolic Panel:

ALT 18 (5-45)

AST 78 (20-60) *High

Allergy Testing

Bertrand was seen by an allergist/immunologist. He received a scratch (IgE) test for the most common allergens, including: dog, cat, tree pollen, grass, mold, egg, wheat, dairy and soy. There was no reaction after 30 minutes. (We kept an eye on the ares for the following 3 days for good measure. The bottom right histamine control scratch was the only welt and it did react like it was supposed to.)

YAY! According to the immunologist, Bertrand does NOT have allergies!

9 Month Post-Infusion Report

Dear Dr. Kurtzberg,

It's been about 9 months since Bertrand's stem cell infusion. He is the happiest and most interactive he has ever been in his life! We don't know whether it's new medication (depakote), the stem cells or what, but, whatever the cause, we are extremely grateful.

Bertrand's most recent CMP on 5/27/11 had his ALT at 26 (normal range: 5-45) and AST at 63 (normal range: 20-60). This normalizing trend has continued in spite of increases in depakote. (His AFP is normal but his GGT is still elevated at 86, with a normal range of 4-15.)

In addition to his continued liver improvement, his smiles and his laughter, Bertrand has been re-learning skills and picking up new ones. He is learning to us eye gaze, as well as switches, to communicate his desires. He is vocalizing (I believe he has a word for Mama). He can raise his arms above his head for the first time, and he is again taking steps when supported or in a gait trainer.

He recently completed his first year of preschool and all of his teachers have remarked on the pronounced, positive changes they've seen in Bertrand since he started. We are very proud of him. :)

Warm regards,
Cristina Might

A pleasant genetic appointment!

Bertrand takes his official ring bearer training VERY seriously!

Bertrand's "good news" roll continues! At today's genetic/metabolic follow-up, Bertrand was found to be "improved", much to the puzzlement and pleasure of his geneticist.

(I was over-the-moon when he declared Bertrand "stable" 6 months ago, so you can imagine my joy at hearing the word "improved"! And follow-up in TWELVE whole months!)

We discussed additional genetic testing, but decided to wait as these tests would be subsumed by the results from Bertrand's full genome sequencing being done at Duke University.

Given that Bertrand has responded well to treatment, a battery of blood tests were drawn to identify new treatment options such as supplements and hormone therapies.

Fortunately, these are not an option for Bertrand because all of his hormone blood levels have been found within NORMAL range! Including Bertrand's AFP for the first time!

• AFP 6.5 (normal range: 0-15)
• Vitamin D 80 (normal range: 30-80)
• Prolactin 15.1 (normal range: 1-16)
• TSH 2.40 (normal range: 0.7-6)
• Free T4 1.18 (normal range: 0.7-2.4)
• Cortisol 10.6 (normal range: 1-23)
• ACTH*
• IGF 1*
• IGF-BP3*

(* Signifies a pending result.)

Bertrand's weight, however, was NOT in normal range. At 39 lbs. 10 oz. he is obese, and he has to be about 10 lbs. lighter! Bertrand needs a weight loss regimen, so the dietitian, food diary, gram scale, and calorie counting are baaaaaack.

(I had a talk with Bertrand regarding the merits of crawling, because I hear that weight just flies off kids once they do, and then Mama won't have to limit his food. I'd like to believe he is taking my suggestion under consideration.)

6 Month Post-Infusion Report

Bertrand thinks he's pretty cool in his sunglasses!

Hi Dr. K,

Bertrand is still doing really well. He can play with sensory bins, track objects perfectly, find/recognize faces, and keeps making progress on bearing weight and using his fingers. The most important change for us is that he is finally happy! He laughs and smiles every day!

Worth noting, in January Bertrand's liver function levels had drastically decreased. They are still elevated (AST 83 and ALT 98), but that's a long way down from being in the 600s! We're not sure if that's thanks to medication (actigall) or possibly stem cells but, whatever the case, we are pleased.

Thank you!

Cleveland Clinic MRI Report

EDIT: The "lay interpretation" is that this is about as good a report as we could expect. Findings are mostly, and confoundingly, normal. :)

* * *Final Report* * *

DATE OF EXAM: Jan 6 2011 1:32PM

MRI BRAIN WO CONTRAST
MR SPECTROSCOPY OF THE BRAIN

PROCEEDURE REASON: Epilepsy and recurrent seizures

INDICATION:
Intractable epilepsy and neurodevelopmental delay

RESULTS:
There is bilaterally symmetrical, nonspecific T2/FLAIR hyperintense areas noted in the periventricular deep white matter adjacent to the atrium of bilateral lateral ventricles, extending to the occipital lobes. Compared to multiple prior outside MR studies, there has been interval increase in size of these abnormal periventricular lesions. Small T2 hyperintense white matter foci are also seen within the left front centrum semi ovale (series 5, image 7), nonspecific in nature. No other parenchymal mass, mass effect or extra-axial fluid collections are identified. Diffusion weighted images demonstrate no evidence of restricted diffusion.

The ventricular system is normal in size, shape and configuration. The cortical sulci are unremarkable. No abnormal intra- or extra-axial fluid collections are identified. The midline structures are unremarkable. The cerebellar tonsils are above the foramen magnum. The myelination is appropriate for age.

The major intracranial vessels are patent. The visualized portions of the orbits, paranasal sinuses, and mastoid air cells are unremarkable.

MR Spectroscopy: Multi voxel MR spectroscopy images demonstrate normal pattern. No evidence of abnormal neuronal activity or increased lactate formation is identified.

IMPRESSION: Bilaterally symmetrical, periatrial T2/FLAIR hyperintense deep white matter signal abnormality. There has been mild interval progression of this abnormality compared with multiple prior outside MR_s. No specific associated MR spectroscopic changes. The MR features are nonspecific and the differentials include metabolic, mitochondrial and dysmyelinating disorders. A contrast enhancement MRI may be performed if there is clinical concern for adrenoleukodystrophy.

3 Month Post-Infusion Report

Starting early November, our family started to receive "gifts" that are possibly the courtesy of stem cells. This is the three month post-infusion report to Dr. Kurtzberg, who conducted Bertrand's autologous stem cell infusion at Duke University in late August 2010.

Hi Dr. Kurtzberg,

I've been putting off this email because I didn't want to "jinx" the small, positive changes Matthew, Bertrand's therapists, and I have seen in Bertrand. ;) Up to this point, there has been no change in his medication, therapy or other interventions (but he'll be starting a new AED next week because there has been an increase in seizures since his steroid wean). That said, here are some of the changes we've seen, starting early November.

• Improved eye contact
• More frequent vocalizations and greater range
• Less extraneous movement (he feels more stable and calm)
• Playing with new toys
• Opening hands more (not as fisted) and will brace himself
• Using fingers
• Posture is more relaxed, with shoulder forward and arms down
• Initiates trying to get up or change position
• Can abdominal crunch to get into sitting position
• Can wipe at his nose
• Things such as a stuffy nose now bother him
• Enjoys getting his hair brushed, being touched
• Engaging in more stiming behavior - teeth grinding, rubbing textures, playing with things

We don't know if these changes were natural, the result of the infusion, or what, but we are grateful for them. I've spent over 2 years working with Bertrand, every single day, on improving his sitting and having his shoulders forward, to then one day have him spontaneously start doing it on his own?! It is fantastic!

Thanks and happy holidays!
Cristina

Falling down

Bertrand took a tumble out of his high-chair and landed in the ER.

This lead to the world's strangest conversation:

Physician: "The CAT scan shows significantly enlarged ventricles, indicating brain damage."

Us: "OK, but what about his bones? Are there any breaks?"

Physician: "Um, his bones are fine."

In 30 years of emergency medicine, the ER doc had never seen a calmer response to the announcement of brain damage.

In more detail, the fall didn't cause the enlarged ventricles.

Actually, beyond bumps and bruises and panicked parents, the fall didn't do anything.

His ventricles (empty space in the brain) began enlarging as his white matter started disappearing about two years ago.

Unfortunately, they appear to be significantly enlarged from his last MRI in December.

Hopefully, with this new data point, we can start to measure life expectancy.

There are a few wildcards in the mix--like the stem cells and the steroids and the ACTH--but it appears we're not winning the war.

We'd been getting optimistic as of late.

We recently turned the tide on his liver damage. The ACTH stopped his seizures for almost two months, giving us a brief and unforgettable snapshot of a happy, loving baby boy.

But, it seems he's still losing white matter.

Clinically, this is consistent with our current hypothesis: male Rett syndrome from somatic mosaicism caused by a de novo mutation. (Somatic mosaicism means part of him is normal, part of him is a mutant; de novo means neither Cristina nor I are a carrier--it's a mutation unique to him.)

His next MRI will be more conclusive about the effects of our efforts, but today was a sober reminder that the clock is ticking.

Post-Infusion Report

Bertrand receiving his stem cell infusion.

The past two weeks have been surprisingly easy for Bertrand, but tough on his mom and dad. Thanks to all of you who sent thoughts of love and support our way. We couldn't have done it without you. :) We apologize for the lack of an update following such a big event for Bertrand.

Bertrand underwent an autologous hematopoietic stem cell infusion on Tuesday, August 24 at Duke University. In other words, he was given stem cells from his very own umbilical cord blood collected at birth.

Umbilical cord blood consists primarily of red blood cells, white blood cells, platelets, plasma and there are a few hematopoietic stem cells in this mix (in Bertrand's case, a meager 160 million). When a child's cord blood is "banked", the processing center does its best to harvest and save the hematopoietic stem cells through centrifugation, which stratifies the cellular components. Dimethylsulfoxide (DMSO) is then slowly added as a cryoprotectant--a type of cellular antifreeze--and just the stem cells, with a few sneaky red blood cells and plasma, are frozen.

[NOTE: DMSO is the stuff which made Bertrand smell like creamed corn for over 24 hours after the infusion. It is also the reason why Bertrand's IV was first filled with benadryl and solu-medrol, a steroid. Around 1% of kids are allergic to DMSO and you don't find out until the infusion begins. To prevent an allergic reaction to DMSO from occurring during the infusion, patients are preventatively treated for allergic reaction. Which in Bertrand's case meant he slept through the entire thing!]

A bag full of hope: 160 million stem cells.

Why save just the stem cells***? They are the cells capable of differentiating into a diverse range of specialized cell types. And amazingly, they have a propensity to specialize and repair at an area of insult, such as an area of the brain damaged by oxygen depravation.

With Dr. Kurtzberg at the forefront, researchers have been studying this phenomena: that stem cells specialize when they reach areas of insult (injury) in the body--in particular the nervous system (spinal cord and brain). Our understanding of this mechanism is growing rapidly with advances in science, but there is a great deal left to learn, since it varies greatly by individual and injury. What this means, using cerebral palsy for example, is that two children with similar brain injuries can have vastly different outcomes.

Currently there are autologous stem cell infusion trials for cerebral palsy (now in phase 2 clinical trial), hydrocephalus and a general study. (Bertrand falls under the general study.) Dr. Kurtzberg at Duke University hopes that through the double blind trial now underway for cerebral palsy, we may soon learn more about the way autologous hematopoietic stem cells behave, and their effectiveness.

Even though study results haven't come out, one of Dr. K's pending studies speaks loudly to what results may look like. Researchers under Dr. K will be infusing young infants believed to have a predisposition for cerebral palsy (due to some kind of trauma etc. during gestation or birth) with autologous stem cells shortly after birth. Treating these infants proactively, if you will. Reading between the lines, I can see that researchers see a lot of promise in these stem cells and their behavior the earlier in development that they are infused.

Bertrand played and watched Elmo through IV placement and slept through the infusion! This was the easiest procedure he has ever had!

Back to Bertrand! Dr. K was very frank with us from the beginning that we should not expect much, or anything. She is still under the impression that Bertrand's case is an undetermined, inborn error of cellular metabolism and this is the cause of his ongoing brain damage. In such a case, Bertrand's infused stem cells would contain the same genetic error found in his existing cells, resulting in either no change or a temporary one. Bottom line, if we are going to see results, we will see them in three to six months. We won't know what form these results could take until/if we see them. Regardless, we have to email Bertrand's progress every 3 months and return for a follow-up exam at Duke in one year.

TIME MACHINE:
In April 2009 we made our first pilgrimage to see Dr. Kurtzberg at Duke - if she could diagnose and treat Bertrand's then assumed lysosomal storage disorder.

In September 2009 we returned to Dr. Kurtzberg as a follow-up and because Bertrand's neurological condition continued to deteriorate.
In August 2010, we simply infused Bertrand's with his umbilical cord stem cells because his condition had stabilized and it wouldn't hurt.

----------

***With the prevalence of cancer in today's world it's shocking to me that all cord blood stem cells aren't systematically banked. When an individual with leukemia undergoes a bone marrow transplant, they are really receiving a stem cell transplant. The stem cells found in the bone marrow of a donor--hematopoietic stem cells, mesenchymal stem cells and endothelial stem cells--are transfused with the expectation that they'll go and take up residence where the patient's own bone marrow has been killed by radiation. However, the stem cells found in cord blood are considered superior to the ones found in adult bone marrow. Since the hematopoietic stem cells prevalent in cord are more primitive, when used in place of adult bone marrow stem cells, there is a lower incidence of Graft Versus Host Disease, easier HLA matching, and a host of other advantages. If you don't bank your child's cord blood PLEASE consider donating it to a public bank! Otherwise these life-saving stem cells are tossed away after birth as medical waste!

Liver Electromicroscopy Results = HOPE!

An example of a liver viewed through electromicroscopy.

Brace yourself. According to Dr. Theodore J. Pysher, Division Chief of Pediatric Pathology, electromicroscopy of Bertrand's liver cells are...

NORMAL

Yes, normal! Bertrand has fibrosis (scaring) but the cells in his liver show no sign of a mitochondrial condition, a storage disorder or inclusions such as those found in Lafora and Unverricht Lundborg Disease.

When Bertrand's new gastroenterologist (who I LOVE) gave me this news I wasn't sure whether to laugh or cry--so I did both. Then of him and Bertrand's geneticist I asked the following question: "where do we go from here?"

1. Ursodiol - Bertrand was started on this drug today to prevent further liver damage.
2. Infection - Fibrosis and subsequent elevated liver enzymes may have been caused by some sort of early infection. We will be looking for evidence and treatment.
3. Alpha-fetoprotein (AFP) - Once in the 1000's, Bertrand's AFP levels have steadily decreased to the brink of normal (34). This could support the infection hypothesis.
4. Prolonged QT - Even though this heart condition is not good, it is a good clue. Combined with epilepsy, prolonged QT implies a channelopathy.
5. Channelopathy - A disease caused by disturbed function of ion channel subunits or the proteins that regulate them. May be either congenital (resulting from a mutation in the encoding genes) or acquired (resulting from autoimmune attack on an ion channel).
6. Valproic Acid - Also known as depakote, this drug is used successfully with a range of channelopathies. Unfortunately, it is hard on the liver.
7. Carnitine - This compound is used in the body for metabolism. By supplementing with carnitine, depakote's liver toxicity may be minimized.
8. Duke/UNC/NIH - Additional institutions following Bertrand's case and care which we will contact to see if there is additional input or interest to do enzyme analysis.

Today's EEG - Not so good?

Some days I resent my MD from wikipedia. Today is one of them. I wish I were one of those parents who could blithely go along with doctors and accept what they're told... Not really. That would be a heck of a lot easier than the hell I am putting myself through today, but someone needs to be awake at the switch for Bertrand's sake. Apparently that person is me.

Okay, enough preamble. What did Dr. Mom get from Bertrand's EEG today?

First of all, and this should be obvious, sleep deprivation for a child with epilepsy is a BAD idea. This is the first EEG Bertrand has been sleep deprived for and it sucked. I guess for most kids it helps them fall asleep and not move as much, but let's be honest with ourselves here: Bertrand has a movement disorder. His last sleep study confirmed that he moves almost as much asleep as he does awake--which is saying something. Furthermore, rather than seeing the new, improved Bertrand we got the old, seize-y, exhausted Bertrand. His new EEG looked like this:




Could this be slightly better than his older one? You be the judge.

Secondly, this EEG confirmed that Bertrand has photosensitive epilepsy, which we suspected. During the intermittent photic stimulation Bertrand's EEG looked like this:



Now, what had me really upset about this EEG wasn't the brain portion as much as Bertrand's electrocardiography (ECG or EKG) line, which is an interpretation of the electrical activity of the heart, during this EEG. Whenever Bertrand moved or sighed really big the EKG would hitch a little (which is normal) but during this period Bertrand was completely STILL. Here is the series of images of that over a period greater than a minute--look at the red EKG line on the bottom.







At first I thought that there was something wrong with the contact on B's chest, but as you saw, the EKG returned to normal on it's own. Since there was no video recording of this EEG, the technicians were under the impression that Bertrand had simply been moving or fussy during this period--which wasn't the case! Bertrand hadn't moved at all! So now I am faced with the decision of whether I should bring this up to B's neurologist. I happen to know that Bertrand's echocardiogram done at Duke was perfect. Will his neurologist think I am crazy? a pest? Or even worse, could this serve as a red herring, causing her to take even longer to adjust Bertrand's treatment? I really don't know if I should say anything. I'll have to consult with my favorite neurologist first.

Based on this EEG, I think that Bertrand may still be on track for trying ACTH treatment for his seizures (which would require coming off the ketogenic diet first). Furthermore, whether or not there were any changes in the EEG doesn't matter because, as my daddy always says, "you must treat the patient, not the EEG." Bertrand HAS improved over the last few months: he is more stable, he is smiling, he is laughing, he is more verbal, and overall his quality of life has improved significantly. And, that's what matters.

UPDATE: Whew! Spoke with my Dad in regard to Bertrand's EEG. The EEG is still highly abnormal (duh) but he thinks the one bad EKG episode may have been due to electrical interference from another electrode, since Bertrand was having a particularly bad subclinical seizure. Part of what suggests this is that the red line went from resembling an EKG line to resembling an EEG line, the other part is that Bertrand is still alive. Lovely.

MRI and MR Spec Results

MRI: BILATERAL ABNORMAL SIGNAL INTENSITY THROUGHOUT THE PERIATRIAL WHITE MATTER. IMAGING FINDINGS ARE SYMMETRIC IN APPEARANCE. FINDINGS ARE SUGGESTIVE OF A TOXIC/METABOLIC WHITE MATTER INJURY PROCESS. ADDITIONAL CONSIDERATIONS WOULD INCLUDE REMOTE ISCHEMIC INSULT. IMAGING FINDINGS ARE NEWLY CONSPICUOUS COMPARED TO THE PREVIOUS STUDY.

MR Spec: NONSPECIFIC SPECTROSCOPY WITH ELEVATION OF THE CHOLINE PEAK SUGGESTIVE OF CELL MEMBRANE TURNOVER. THERE IS QUESTIONABLE PRESENCE OF A LACTATE PEAK BURIED WITHIN THE BASELINE NOISE.

Lab Results: AFP: 102.5 (normal range: 0-15); ALT: 312 (normal range: 5-45); AST: 263 (normal range: 20-60)

Doctor's Take: "There are no changes since the evaluation done at Duke University [April 2009, age 16 months], but there are changes compared to the initial MRI done at PCMC [August 2008, age 8 months]." And, "This pattern is totally nonspecific and does not guide us further. I looked for abnormal peaks on the MR spec and there are none."

Our Take: Breaking down the medical jargon, what does "remote ischemic insult" mean? Remote means it happened long time ago. Ischemic means due to circulation (or lack thereof) and insult means brain injury (stroke and embolism are in this family). And my best guess for "periatrial white matter" is the that they meant "periventricular white matter" or the part of the brain with myelinated axons surrounding the ventricles (which contain the CSF) in the brain. Someone please correct me if I am wrong!

(Or, as Prof. Might likes to put it: grey matter is the CPU and white matter is the networking cable. Bertrand appears to have a networking problem.)

Since there has been no change in the MRI since April 2009, even though these findings are suggestive of a metabolic injury process, this also opens up the possibility of ischemic insult (for which Bertrand's cord blood could be used as a therapy) as a possible cause of Bertrand's issues. Unfortunately, this means the field has been widened instead of narrowed, and time may be the only determinant.

24-Hour EEG Results

Oh yeah, I forgot to mention that Bertrand's 24-hour EEG was read yesterday by four neurologists, including Dr. Colin Van Orman, an epileptologist. Bertrand's EEG was highly abnormal. There was lots of noise, focal seizures and generalized seizures. Bottom line: they all agreed with the April 2009 Duke University finding of multi-focal epilepsy.

Let me take a moment here to explain something that until a few months ago was not clear even to me. Conditions like epilepsy and autism, both of which Bertrand has, are really symptoms, not stand alone diagnoses. Like a runny nose can be caused by viruses, bacterias, allergies, genetics, etc., so too can epilepsy have a variety of root causes. The same goes with autism. In Bertrand's case the root cause of both is believed to be an undiagnosed genetic disorder.

UNC/Duke Report

Last week was an informative one! The experts in Neurodevelopmental Function in Rare Disorders at UNC and Medical Genetics at Duke are top notch. One leaves their clinics with so much new information (so much of it actionable) that it is a little bit overwhelming. That said, I'll do my best to summarize what we learned.

From UNC:

Dawn, physical therapist

• She said Bertrand is very close to being able to get to sitting on his own.
• She said he needs to practice getting off his y-axis: trunk rotation, balance, coordination.
• She said he needs to stand while weight bearing on his arms.
• She said he needs to reduce his back arching.
  

Sheryl, speech therapist

• Sheryl is a new therapist with the NFRD group with little to no experience adjusting cognitive and linguistic tests for kids with physical limitations.
  
• She tested Bertrand differently from the prior speech therapist at NFRD and found cognitive and linguistic regression (now 6 month-old level) in him.
• Both Dr. Escolar and I are focusing on findings from the parent questionnaire, which shows he has developed significantly in these areas since last time.
  

Dr. Holly Martin

• She would like to see Bertrand closer to 25 percentile weight.
  
• She suggested working with a nutritionist to attain weight and nutritional goals.
  
• She provided thickening medium to add to fluids to encourage drinking from a cup.
  
• She would like an EEG as Bertrand's absence (petit mal) seizures are worsening.
  

Dr. Maria Escolar

• She does not trust the negative oliggosaccharide (a.k.a., GAGs) screen as it returns high false negatives and would like it retested at the UAB lab.
• If the Glycosaminoglycans (GAGs) return elevated, she recommends working with a biochemist to back solve for which enzyme Bertrand is missing.
  
• Due to concerns about Bertrand's basal ganglia, she would like to see an MRI in October, 6 months after his last MRI.
  
• She would like to see Bertrand tested for Pelizaeus-Merzbacher disease (PMD).
• She mentioned that if Bertrand's condition is one of the metabolic ones then standard anticonvulsants (seizure medicaitons) won't work well if at all.
• She sees Bertrand's inability to self-soothe as the biggest immediate concern and one we should work feverishly on.
  

From Duke:

Dr. Vandana Shashi

• She said that Bertrand does not have microcephaly. Both measurements taken at Duke placed him between the 10th and 25th percentile. (Yay!!!)
  
• She thought that Allgrove syndrome was not out of the question and ordered genetic testing for it.
  
• She requested and drew additional DNA from Bertrand to use if she comes up with additional tests she'd like done.
  
• She said that Bertrand seemed very improved and would venture that his condition may not be neurodegenerative. (Yay x2!!!)
  
• She noted that his seizures were worse and attempted to get an STAT EEG at Duke, but unfortunately the hospital was full.
• She believes that a trial of anticonvulsant, with little to no liver involvement and liver monitoring, is called for.
  

Dr. Joanne Kurtzberg

• She candidly said that can't help him.

This post is not perfect. I will try to add more items as I remember them. I also can't forget to mention that, while there, we had a fantastic time with our North Carolina family! Kelly, Rob, Julie, Ben and Luke--Thank you!

FINALLY! MECP2 Gene Test Results!

"Rett Syndrome: Negative. No mutations detected in the MECP2 gene."

While I'll admit I did a 5 second happy dance, unfortunately, this is not as straightforward as it seems. (A) While MECP2 mutations count for something like 95% of all Rett syndrome cases, there are two additional genes it could be. (B) The fact that Bertrand is MALE and ALIVE and NORMAL 46XY means that if he did have Rett, he has a form of somatic mosaicism: part of his body has the mutated gene while the other part of his body does not. His blood, the part of his body on which the gene was tested, could simply be part of the portion of his body with the unmutated MECP2 gene.

Moving Forward: Blood Work & 24-hour EEG

We are regaining momentum on the search for Bertrand's condition.

Yesterday, Bertrand's blood was drawn for hepatic (liver) function tests and the MeCP2 gene sequencing for Rett syndrome. Bertrand's liver function came back as still elevated: albumin 4.0, ALT 324 and AST 188.

The results for the MeCP2 will be back in about 21 days. If that comes back normal, we'll test the CDKL5 gene; one responsible for atypical Rett syndrome. Then, if that is normal, we will order testing for the final atypical Rett gene.

Frustratingly enough, in digging through my email for this post, I found an email from Dr. Vandana Shashi of Duke University to Dr. Longo from April 2009 recommending, "MECP2 sequencing if microarray is normal." Argh. She recommended testing for it almost 5 months ago and I missed it. :( I am going to walk back through her additional recommendations to make sure I haven't missed anything else.

Bertrand's 24-hour EEG should be scheduled for or by the middle of next week when Dr. Longo is back in town. This will shed a lot more light on what his brain activity looks like and what medications we should consider.