June 29, 2014

"Parental Might"

Our family was recently featured in the summer issue of Sanford-Burnham Medical Research Institute's "Portal".  It's a lovely feature on pioneering N-glycanase deficiency research through Dr. Hudson Freeze's laboratory and the Bertrand Might Research Fund.  

We began funding Hud's NGLY1 research in mid-2012, and went to visit the lab shortly thereafter in August 2012.  Our fabulous post-doc Ping He has done and continues to do a great job pushing the science for our kids.  We're proud to support the Freeze lab.  :)

June 24, 2014

Introducing Winston

Winston John Might arrived on June 19th.
He was born a hefty 8 lbs. 7 oz. and 21 inches long.
We're all smitten and glad to be a family of five.

June 13, 2014

NIH, Day 5

Today was the end of Bertrand's second visit to the NIH.

Bertrand was in very high spirits all day long.

Here's a photo of him playing at the Children's Inn the night before:

Of course, Bertrand started the day in the sleep study room loaded up with EEG electrodes and respiration belts, continuing the study from the night before.

I watched him until 1:30 AM, and then Nana took over.

Nana captured a "looping seizure" on the EEG at 3:33 AM to 3:47 AM.

Nana said the EEG looked almost black with activity during the episode.

The EEG tech on duty said, "Oh yeah, we're definitely getting this."

I hope the neurologists have the data they need to determine what these bizarre episodes are.

At 5:00 AM, the metabolic team came up to measure Bertrand's resting metabolic rate.  To do this, they wrapped him in an airtight bubble for 30 minutes.

They pumped air in and measured CO2 going out:

By measuring the "exhaust" expelled from the body at rest, they can calculate exactly how many calories the body is burning, and extrapolate to find Bertrand's baseline metabolism.

They measured it at 735 calories per day at rest.  What's interesting is that Bertrand's metabolism should be at 950 calories per day based on height and weight.

I asked about the discrepancy, and the theory at the moment is that Bertrand's lean body mass is lower than average for his height and weight, which would lower his natural metabolic rate.

It is possible, of course, that the discrepancy could be in part due to some factor related to NGLY1.

If the finding is consistent across other NGLY1 patients that don't have as much "adiposity" (chunkiness) as Bertrand, then it could be linked to the condition.

I may also take Bertrand to the "bod pod" device on campus at the University of Utah to see if we can measure his true lean mass content, which would give us a sense if there as a real discrepancy or not.

Bertrand managed to sleep right through being bubbled and unbubbled.

His IV stopped returning blood again, so they had to do an individual blood draw in the morning.

This time, we got Tony, a nurse in the pediatric unit.

Tony did the best blood draw on Bertrand ever.

Not only did he not use an ultrasound, Bertrand never even cried when Tony held his arm and probed it for veins.

He inserted the needle so gently that Bertrand didn't even notice!

He got blood on the first try.

We will ask for Tony on the next visit to NIH.

After the blood draw, it was off to clinical photography.

Bertrand sat for a new photo session to capture as much of him as possible.

They pulled up his 2009 NIH photos to capture the same shots for comparison.

After that, we went to the pediatric clinic for a developmental evaluation.

They took Bertrand behind a one-way mirror, so that we could watch him during the test, but he couldn't see or hear us:

It was nerve-wracking watching Bertrand do the tests, since he was truly on his own.

Luckily, Bertrand brought his A game.

He was happy, engaged, sweet, charming and focused for all the tests:

He rocked it.

They're still evaluating his score, but the specific score doesn't matter to me.

It was his best evaluation ever.

We headed back to the room after that for some rest and play:

 Bertrand has really enjoyed playing with his toy dog Scout.

A dental exam found only that Bertrand ground his teeth.  His teeth are otherwise healthy.

Dr. Zhang, a fellow from endocrinology, wanted to do a follow-up visit with Bertrand.  

He did a full exam on Bertrand, and seemed interested in trying to characterize the differences between Bertrand and endocrine disorders like AAA / Allgrove.  (Bertrand was originally admitted to the NIH in 2009 under suspicion of Allgrove.)

After Dr. Zhang finished, a physician specializing in movement disorders came in to video record Bertrand's fascinating movements.

After that, Dr. Lyons returned, since some of the early immunology values had come back with curious data and conducted a brief exam to check for predictions based on that data.

At the same time, I headed down with Donna Krasnewich, Lynne Wolfe and Christina Lam for a debriefing on the visit.

They passed me a stack of reports about 3/4 inches thick, and said they'd be sending a phonebook of more results in about a month.

Research results will trickle in over months or years.

Donna brought insights from years of CDG experience into the wrap-up.

Among those insights, she was able characterize the ways in which NGLY1 deficiency is a true CDG  and the ways in which it is different and interesting.

It is exciting to have folks like Donna involved in the rapidly evolving NGLY1 story!

I'll share more on the wrap-up in a future post as well.

We stepped through the findings (which we'll share in more detail later) going system-by-system throughout Bertrand's entire body.

The week is jam-packed with specialists all over the place, so to see these appointments start to coalesce into a holistic view of Bertrand's entire body as an interconnected system was incredible.

Bertrand has seen many hospitals, but this was the first time a hospital saw Bertrand.

There were many new discoveries and many confirmations (to be shared soon).

As an example of just one "holistic" finding, the sweat test was order because Bertrand has abnormal tear production, and an endocrinologist pointed out that tear ducts and sweat glands have a common embryological origin.

He hypothesized that we should see poor sweat production too.

And, we did: the sweat test conducted by an electrophysiologist showed low sweat production!

That discovery takes us much closer to understanding the true nature of Bertrand's lack of tears.

One of our biggest problems with Bertrand's care -- especially early on -- was that his care was being stuck in silos.

Neuro folks talked to neuro folks.  Liver folks talked to liver folks.  Eye folks talked to eye folks.

At NIH, results cross boundaries so that observations in one specialty become hypotheses in another which turn into tests and experiments in yet a third.

And, the speed with which all of it happens is stunning.
We'll have a follow-up post on the process and its findings, since it's hard to do it justice in the daily summaries alone.

In a nutshell, the NGLY1 community is beyond lucky to have the opportunity to be a part of this research program.

As more and more NGLY1 families participate with the NIH and feed the results into the NGLY1 research network, it's going to push the science forward for these kids farther and faster than ever before in the history of rare disease.

Each child that comes here takes one giant leap forward for all the rest.

We have to say a big thanks to all of the professionals that cared for Bertrand this week and to the NGLY1 researchers submitting tests to be run, but we owe a massive thanks to Lynne Wolfe and Christina Lam for putting in what must have been weeks (or months!) of their lives planning for Bertrand's visit.

When I started to look back at all that was accomplished in this week and all the planning they put into this visit on Bertrand's behalf, I couldn't help but feel humbled and grateful.

At the end, I took 27 pictures of the Lynne, Christina and Bertrand.

Bertrand was almost not a blur in this one:

June 12, 2014

NIH, Day 4

Day four was lots of consults with specialists for the preliminary data collected yesterday and more data collection in the afternoon and night.

We started off with another clogged IV for the blood draw.

(It has always been difficult to draw blood from Bertrand, and we're wondering if the same is true for other NGLY1 families.)

Our first meeting of the day was with neurologist Andrea Gropman, Division Chief of Neurogenetics at Children's National.

Andrea took a thorough neurological history for Bertrand, and then examined him in detail.

She was particularly interested his development, his seizure types, his movements and his medications.

She noted that his movements are unusual and are difficult to classify under the traditional taxonomies for movement disorders: it's not quite ataxia and not quite chorea.  (We've heard this many times before.)

She also recommended specialists that might be able to work with his unusual presentation.

After that, we met with Carmen Brewer in audiology.

She explained in significantly more detail the exact nature of Bertrand's auditory problems.

Mechanically, Bertrand hears well.  Electrically, it's a different story.

To my eyes, his ABR showed a "damped waveform," in which the characteristic peaks become increasingly difficult to distinguish as they go on.

Carmen explained that people with this kind of "auditory neuropathy" can hear, but that complex sounds such as speech may be difficult to process.

It's possible he recognizes the tone or cadence of our voice, but the words come out as gibberish.

Music, on the other hand, when it's melodic, periodic and repetitious, may be easier for him to process.

This could explain why Bertrand loves music (and always has), but doesn't respond to a dog barking right behind his head.

It's not that he doesn't hear the dog: he may simply not understand the barking at all.

After meeting with Carmen, we did a pit stop for Bertrand in his room and tried to get blood from his new IV from yesterday.

No blood.

The nurse tried everything he could to get blood out, but nothing worked.

We had to get blood within an hour and a half in order to get it on a plane to California in time, so we were scheduled for another ultrasound-guided IV.

In the meantime, we headed to meet with Wadih Zain, the ophthalmologist, knowing we'd have to bolt as soon as we got the call to go to IV ultrasound.

Wadih re-ran the Schirmer's test for moisture in Bertrand's eyes:

And, this time, his eyes came out very dry!

So, under general anesthesia: wet; awake: dry.

After that, we got the call for the IV, since we only had 30 minutes to get the blood shipped.

Once again, one vein, one shot, one direct hit.

This was the easiest and best yet.

Bertrand filled the tubes with 10 minutes to spare.

From there, we headed to the EEG lab to do lead placement and a 20 minute waking EEG:

Bertrand smiled and giggled almost the whole time:

After that, we had the sweat test and an electromyography exam (EMG).

The sweat test uses light electrical stimulation to excite the sweat glands and measure sweat production:

Apparently, kids sometimes cry or flinch during the sweat test.

Bertrand got uncharacteristically still.

We were worried that it had triggered an absence seizure, so we touched him, and he instantly looked up, smiled and happy hooted.

The physician gave us a confused glance.

She had never encountered a child that seemed to be calmed by the process.

An EMG involves electrocuting nerves in the leg and arm to measure conductivity.

Bertrand had an EMG at Duke, and it found peripheral neuropathy at the time.

The EMG is a critical test because there appears to be demylenation with NGLY1, and we need to know how much.

Right after the EMG started, 36 hours of constipation came to an abrupt end.

Bertrand was characteristically upset for the next 10 minutes, but then passed out for the remainder of the EMG, including the brief needle test.

After that, we took him back to the Children's Inn for cleanup and playtime until his sleep study / EEG starts tonight.

Papa brought some delicious crabs and shrimp for dinner.

After that, we headed back for the overnight EEG / sleep study:

Bertrand hasn't been thrilled with most of the other tests, but he felt strongly that a "sleep study" was an area where he could perform.

As I write this, he's been sound asleep for about an hour.

We're looking for signs of sleep apnea and for seizures.
I'm on the first shift. Nana is on second.

In the times we met with Lynne Wolfe today, she shared more of the early lab findings trickling back.

In particular, we got the first evidence that Bertrand may also be suffering from secondary mitochondrial dysfunction, as some other NGLY1 patients do.

This is an exciting development, and while I wouldn't wish mitochondrial dysfunction on any other NGLY1 patients, finding more consistency in the phenotype is highly informative.

June 11, 2014

NIH, Day 3

Today was the day Bertrand went under general anesthesia for a battery of procedures.

It was a hard day for Bertrand.

Bertrand had a good night's sleep, even though his IV kept kinking up and bringing the nurse in to fix it.  (He slept right through it each time.)

His day started at 6:30am:

They couldn't pull his blood at 7:00am because his IV was letting fluids in, but not out.

Fortunately, since fluids were still going in, they didn't need a new IV for anesthesia.

I held his hand as he went under for four hours of scans, biopsies and tests.

His orders while out were:
  1. an MRI/MRS scan on his head and brain (90 minutes);
  2. an auditory brain response test;
  3. an opthalmological exam;
  4. retinal photography;
  5. nasal-gastric tube insertion to extract stomach fluids for pH testing;
  6. a Schirmer's moisture test for eye moisture;
  7. a lumbar puncture to extract cerebrospinal fluid;
  8. a skin biopsy from his forearm to grow fibroblasts; 
  9. blood draw; and
  10. a dental exam.

Bertrand always gets eerily still under general.

Bertrand's body, even asleep, is riddled with tiny tugs and jerks.

These little movements have become an almost imperceptible background noise over time.

When that background noise fades out, it's louder than ever.

While Bertrand was under, we met with genetic counseling to construct a family tree annotated with any factors of (possible) genetic significance.

We then met with Dr. Lyons, an immunology researcher.  Dr. Lyons went into detail explaining even more effects of CDGs on the immune system with a focus on allergies.

CDGs are proving to be a fascinating way to study the immune system.  The spectrum of CDGs systematically break individual parts of the glyco-pathways involved in immune processes.

That allows scientists to observe the effects of the breaks at each point and to infer relationships between glycobiology and the immune system.

When Bertrand woke up, he was upset:

Unfortunately, we couldn't feed him yet because the nasal-gastric tube remained, and had to remain until they collected a sample of gastric fluids.  (During the procedure, nothing was coming out of the tube.)

His stomach had a lot of gas.

He calmed down quickly, gave us a few smiles and then passed out.

He woke up briefly to watch some Elmo:

 We had to run a new IV under ultrasound, since his old one couldn't collect blood any more.

Just like last time, they found only one suitable vein.

Just like last time, they got it on the first try.

We tried to feed him when we got back, but he threw up three times.

Zofran settled his tummy, and then he passed out for the evening.

In the afternoon, we had long conversations with Lynne Wolfe and Christina Lam about preliminary findings and hypotheses.

We have some early findings and confirmations:
  1. Bertrand's tear ducts produce normal levels of moisture, yet he never cries.
  2. The dry eyes could be caused by physiological problems with the eyelids.
  3. Bertrand's stomach acids have a normal pH: 1.5.
  4. Bertrand's ears appear to work, but there are processing problems with the nerve leading to the occipital lobe.
  5. There is atrophy in his optic nerve.
  6. There is unexpectedly low protein in his cerebrospinal fluid (CSF).  (Lynne Wolfe explained that if neurons were dying, we would expect that protein to accumulate in the CSF.  This is a going to be an interesting puzzle to solve.)
Many more results are on the way as tests are run on the samples and data collected today.

An intriguing hypothesis

Lynne Wolfe also shared an intriguing hypothesis about a mechanism of harm when thinking about the moisture problems in NGLY1 patients and the possibility of mucin deficiency.

(Mucin is a key protein in lubrication, but it's O-linked. Lynne's hypothesis can explain how an N-linked disorder can create an O-linked deficit.)

What's really interesting about the hypothesis is that it focuses on downstream pathway problems from NGLY1 deficiency, whereas we've mostly been focusing on the upstream (glycoprotein accumulation) problems.

She stressed that it's only a hypothesis at this point, but it points in the direction of interesting tests to run.

If she's right, it also points toward other routes for developing treatments.

I was really intrigued by this possibility, because until now, I'd considered misfolded glycoproteins themselves as the sole source of harm.

Much more work needs to be done to test this hypothesis.

Fortunately, Lynne and Hudson Freeze are already on top of it.

If it holds, it's going to be a big step in the right direction for the NGLY1 patients for both understanding and treatment.

June 10, 2014

NIH, Day 2

Today was about collecting data.

Lots of data.

We spent a good chunk of the morning discussing consents and objectives for the next day's procedures with Christina Lam.

After those discussions, it was off to more testing.

Bertrand was really excited to do his barium swallow test:

I got to watch Bertrand's skeleton drink and chew a radioactive breakfast in real time:

It was equal parts disturbing and mesmerizing.

Bertrand has a suck-to-swallow ratio of 4 to 1, which is developmentally very delayed.

He doesn't chew food so much as he sucks it into tiny swallowable pieces.

When we got back to the room, they attached a urine collection bag.

Then he slept some more:

We had a consult with anesthesia in preparation for about three hours of sedated procedures tomorrow.

Working in Bertrand's seizure medications without him eating will be challenging, but we worked out a plan with his team.

Bertrand will be hospitalized tonight to pump him up on IV fluids.

We left from anesthesia to do a DEXA scan.

They're checking his bone density given his history of fractures:

After that, it was back to radiology for a full abdominal ultrasound.

The ultrasound gel was cold:

Then Bertrand blew out his urine collection bag.  All over the ultrasound tech's table.

It got worse from there, but Bertrand thought it was hysterical:

We spoke again with Christina Lam and had a discussion about the kind of CDG that Bertrand had.

CDGs are usually classified as "Type I" (defects in N-glycan synthesis) and "Type II" (defects in N-glycan processing).

To the extent that "processing" is "cleaving from proteins," Bertrand is a "Type II," and yet this doesn't seem to be a totally fair characterization.

(Christina Lam explained that the typing system for CDG is really based around the effect it has on the polarity of the glycoprotein transferrin.)

Constantine Stratakis brought in a team of students and fellow endocrinologists to study Bertrand.

Back in 2009, Cristina contacted Constantine under suspicion of Allgrove.

Constantine had Bertrand out to the NIH for examination in 2009. They ruled out Allgrove, and took a few guesses at rarer disorders.

Constantine was very familiar with the updates in Bertrand's case, and recommended an ACTH stress test, a sweat test and a few kidney tests.

Bertrand's inability to cry tears combined with his issues with sweating immediately caught the attention of one of the endocrinologists.

He interrupted Constantine to explain that tear ducts and sweat glands have a common embryological basis and that a lengthening in the structure during early development could produce both observed effects.

They also suggested several features to look for in the impending MRI.

After that, Bertrand headed off for an echocardiogram:

That seemed normal, but before we could head back, Bertrand blew out a second urine collection bag all over the examination table.

Another total loss of sample.

Unfortunately, today was the last time we could get a urine sample, since the next day's battery of tests would introduce significant confounding factors into his urine.

When we got back to his room, Lynne Wolfe hand-modified a large colostomy bag to serve as a urine collection bag.

That worked perfectly.

Then Bertrand's IV came loose.

Blood slowly pooled into a bubble under the transparent patch holding it down.

Faster than I could blink, Lynne Wolfe had it redressed and repaired.

Bertrand did a round of physical therapy, showing off the impressive new skills he's learned at school and from Miss Caitlin, Miss Katie and Miss Victoria.

We got a pass for two hours of leave for Bertrand, so we took him for dinner in the atrium:

 and to play at the Children's Inn:

Bertrand has taken his last meal until tomorrow afternoon; he's fast asleep; tomorrow will be a busy day:

June 9, 2014

NIH, Day 1

Bertrand was admitted today under three different research "protocols" at the NIH.

Almost every system of his body will be under intense study by leading specialists for the five days.

There are many research goals, but most are centered around two chief objectives:

 (1) What is Bertrand's phenotype? (What are the symptoms?)

 (2) What is the natural progression and spectrum of his disorder, NGLY1 deficiency?

Because of the second objective, Bertrand is just the first of several NGLY1 patients to be admitted under these protocols.  The NIH needs to study and intends to study as many NGLY1 children as possible as part of this research.

Shedding light on the variations between the patients is critical to understanding, treating and curing the disorder.

Bertrand sleeps

Every day at the NIH will be intense.

Day one was no exception.

We arrived at 7:30am for admission.

Bertrand slept through it:

After that, Bertrand slept through his weigh-in:

Then he slept through his height measurement and vitals:

After that, we met with Lynne Wolfe and Christina Lam for an introduction and overview.  Lynne and Christina have put tremendous effort into developing the protocols under which Bertrand is being studied and into the military-invasion-level logistics of coordinating so many doctors in so little time.

We also briefly met with Bill Gahl, director of the Undiagnosed Disease Program (UDP) at the NIH.  (Bertrand is also being studied under a protocol from the UDP program.)

Bertrand took the opportunity to sleep some more:

The draw

We headed to phlebotomy next, where Bertrand slept while waiting:

until he realized he had to fill every vial on this tray with blood:

In a moment of karmic vengeance years in the making, Bertrand literally (yet quite accidentally) kicked the unsuspecting phlebotomist in the nuts while he drew blood.

Consulting with the experts

We had an excellent consult with physiatrist Scott Paul and occupational therapy specialist Becky Parks.  They were able to provide insight into better therapies and techniques for Bertrand, ranging from better stances for his stander to new equipment to enhance his aquatherapy.  They also recommended a near-total overhaul of his wheelchair, since he is growing much faster than expected.

Next up, we had a surprise visit from Donna Krasnewich, a leading scientist and physician on disorders of glycosylation.  Donna has seen almost every patient out there with a CDG, and she was excited to meet Bertrand, the first known case of a disorder of deglycosylation.

After a thorough inspection, she found many similarities between Bertrand and the traditional CDG patients.

She also found a handful of notable differences.

Discovering these similarities and differences will help scientists understand both NGLY1 deficiency and traditional CDG.

That understanding brings both closer to treatments and cures.

This week is all about building that understanding.


At this point, we'd run out of time for lunch.

Out of nowhere, an angel (Bertrand's "Aunt" Niki Hyer) appeared out of nowhere with a delicious spread from Founding Farmer's:

After that, we headed over to get an EKG (primarily to confirm the absence of long QT syndrome).

The IV team

To avoid ringing the doorbell on any further phlebotomists, they decided to get Bertrand an IV from which they could draw blood freely.

Since Bertrand is a difficult stick, they used an ultrasound to find a vein.

After about 10 minutes of scanning both arms with the ultrasound, the IV tech looked up and said:

"He's got only one vein left."

"And, it's small."

"I need backup because we're only going to get one shot at this."

Some kind of phlebotomist-ninja hybrid was summoned while Bertrand was pinned down to prevent any and all movement.

The hybrid guided the needle in under ultrasound while Bertrand howled and writhed.

Blood squirted onto the table.

They got the vein.

30 seconds later, his IV was wrapped, and we were on our way.


Next up was a full skeletal survey in radiology.

Bertrand slept first:

Then they spent about an hour taking skeletal scans:

The science

After that, we met Bertrand's genetic counselor, and had a long chat with Lynne Wolfe about the importance of these protocols and the valuable information they yield -- for the patients and for science.

In the final meeting of the day, we met with an immunologist researching the peculiar and intriguing immune system properties of CDGs, Sergio Rosenzsweig.

He gave us insights into the way NGLY1 deficiency and other CDGs can influence the immune system.