NGLY1 Profile: Grace, age 4

Patient: Grace, age 4
Parents: Kristen and Matt
Sibling(s): none

History

Grace was delivered via emergency Caesarean section at Lucile Packard Children’s Hospital at Stanford in 2009. The doctors hit the “crash” button because of decreasing fetal heart rate. Grace's Apgars were 4 at 1 minute and 8 at 5 minutes. She spent the first 2 nights in our room at the hospital, but she was extremely lethargic, was not eating, or going to the bathroom. Her eyes looked hazy and quite gray. Her pediatrician ran a series of blood tests and Grace's CRP (a non-specific marker for stress such as an infection) was extremely elevated (~12). The doctors quickly moved Grace to the NICU for a little over 2 weeks.

The doctors ran all kinds of tests on her from a spinal tap to a brain ultrasound to an EKG to multiple stomach x-rays. They never could tell if she had a viral or bacterial infection, but they were fairly sure it was one or the other. Consequently they gave her 2 full weeks of antibiotics and a few days of antivirals. Every 24 to 48 hours Grace improved slightly. It seemed the drugs were working. Toward the end of her 2-week stay, her liver enzymes (known as LFTs for short) were shown to be elevated and her platelet count was dangerously low. The doctors thought this was most likely a residual effect of the infection and sent us home to be monitored as an outpatient (we were told there was nothing more they could do in the intensive care unit). Shortly before Thanksgiving 2009, the liver enzymes normalized and an abdominal ultrasound showed the liver working normally. We felt like we dodged a bullet and we decided to retest at 5 to 6 months of age after working closely with Grace's gastroenterologist at Stanford.

Unfortunately the tests at 5 months showed elevated AST and ALT (GGT was normal). On top of the elevated LFTs, Grace was falling behind developmentally. This is where we mobilized in a big way because clearly this was not a reaction to an infection and was not isolated to GI. This was something very serious and something genetic.

We assembled the best and brightest clinical minds in several disciplines at many world-class centers. We made 3 trips to Columbia, 2 trips to CHOP, 2 trips to NIH, 2 trips to Baylor College of Medicine / Texas Children’s Hospital, 1 trip to University of Colorado, Boulder, 1 trip to John Hopkins, and countless trips to Stanford and UCSF. From the age of 6 months to 3 and ½ years old, we pursued a primary mitochondrial disease.

Whole Genome Breakthrough

After exhausting all of our testing options, two centers (Stanford and Baylor) independently performed whole genome sequencing (WGS). We wanted to see if both came up with the same conclusion independently. Stanford and Baylor came back with the exact same leading gene candidate (SUPV3L1). This gene fit Grace’s phenotype and the theory that Grace’s condition was mitochondrial. We spent nearly 1 year investigating this gene under the close supervision of Dr. Greg Enns at Stanford and Dr. Vamsi Mootha at Harvard / Broad. Unfortunately the functional assays did not prove anything.

In addition to SUPV3L1, Stanford and Baylor flagged several other “candidates” (genes that looked suspicious). We explored several of these, but not all. In February 2013, Kristen, Grace, and I flew back down to Houston for 4 days. Under the guidance of Dr. Huda Zoghbi, we met with over 15 doctors in 3 days. Two of the doctors we met with were Richard Gibbs and Matthew Bainbridge. We asked them to re-run our data. Within a few days of meeting, Matthew emailed asking if Grace produced tears. We had noted to several specialists that Grace did not produce streaming tears when sad or hurt, but this clue didn’t help us over the previous years. Richard and Matthew had flagged one gene in particular (NGLY1). This gene was actually flagged by Stanford back in 2011, but it was a mystery gene. At the time, no databases or medical literature showed one human being having a NGLY1 mutation. Unbeknownst to Stanford and us, the doctors at Duke had diagnosed Bertrand and were preparing to publish. Once they did publish, Richard and Matthew found it. The phenotypes, while not perfect matches, were close. The lack of tears while crying was a significant clue in piecing the puzzle together.

Current Health Condition

Grace is stable. While she has many challenges, she is amazingly happy and resilient. Despite spending a lot of time in hospitals and clinics, she is relatively healthy for a 4 year old NGLY1 patient. Colds affect her more than most kids (her body gets “floppy”), but she recovers quickly. Developmentally she is more like a 12 to 18 month old. She can sit-up, pull-up to stand, “cruise” along furniture, and walk for short distance after pulling up to stand. She cannot talk. She has a few sounds and word approximations. She cannot point and has no pincer grasp (index finger + thumb). Her disease affects her central nervous system (CNS), liver, and muscle predominantly. She has microcephaly (small head), difficulty gaining and maintaining weight, alacrima (dry eyes), sleep apnea, and strabismus (eyes wander). The systems we have to keep close tabs of are liver, eyes, and lungs. The latter has showed some signs of aspiration, which is quite dangerous (pneumonia can be lethal in young kids with chronic / rare illness). Grace loves Elmo, books, music (Katy Perry, Taylor Swift, & Super Simple Songs), Super Grover 2.0, swimming, and horses.

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NGLY1 Profile: Mason, age 5

Patient: Mason, age 5

Parents: Sara and Mark

Sibling(s): none

Mason is five years old and was born at 34 weeks via emergency C-section because of bradycardia episodes, he was measuring small and my fluid level was dangerously low. He was a relatively 'normal' preemie, staying in the NICU for 24 days, his main issues were jaundice, finally passing the merconium, and learning to eat and hold his temperature. He was on oxygen for only the first 24 hours and progressed somewhat normally in the NICU. He had a Hirschprung's test done because it took him longer than 7 days to pass the merconium; but that test came back negative.



Mason came home weighing 5lbs, he cried almost all the time when he was awake, wouldn't sleep for longer than 45 mins at a time and projective vomited almost everything he ate. He was never very good at latching on, so I pumped for 3 months and bottle fed him, until putting him on specialty formula, all of which didn't help. He was tested for allergies and other than having a sensitive to dairy, there was nothing.

Mason never reached any developmental milestones and it wasn't until he was evaluated by Easter Seals and recommended to a neurologist that we knew something was very wrong. The neurologist suspected seizures from the very beginning, noticing his quick eye movements (I honestly didn't believe him because I never saw them). He also never stop moving - ever. It was like he was constantly twitching, but never the same motions over and over, just like his body couldn't ever relax. He was put on Keppra, and obviously because I didn't see the seizures in the first place, I never saw an improvement.

Mason was always a heavy breather, in fact we would joke that he was like Darth Vader. He went in for an MRI after the neurology visit and they refused to put him under because of the stridor. He saw an ENT who thought he just needed to grow a little bigger and hopefully his airway became strong; they attributed the stridor to the reflux. He finally got an MRI, and overall his brain was 'smaller' than normal, but there was nothing significantly glaring - little did I know this meant absolutely nothing!

At about 13 months, he was hospitalized for severe breathing issues; he sounded like he was breathing from a straw. It was at this 5 day stay where they did the muscle biopsy, found that he has only one kidney, and still attributed the stridor to severe reflux; they put him on feeding through an NG tube and his breathing seemed to get better so they sent us home. (Not to mention that they stuck him one million times trying to get an IV so they could fly him, then another million times to do tons of tests...he's one of the toughest little guys ever). They sent us home on a steroid, once he was off the steroid, the breathing got worse, so he was sent back to the hospital to get the Nissen Fundoplication surgery. The hope was that if he physically couldn't throw up, his airway wouldn't be burned by the acid and then his airway wouldn't be inflamed and breathing would improve. During the Nissen, they did a livery biopsy to check to Mito disease. It was after the muscle and liver they told us he had mito - I never realized that when they classified him with this it was because he had too much mitochondria!

Unfortunately, after another round of steroids and being sent home, his breathing was still awful, so they told us he would need to be trached. One month later, he had his trach surgery. We were told he would be kept asleep for a week so that he could heal and wouldn't pull at his trach - they kept him under for only a few hours after surgery and when he woke it was one of the most heartbreaking moments a mother could have, as I'm sure you can relate. For the first two months, we couldn't leave the floor, it was like the best moment of my life when we were allowed to walk around the entire hospital. In total, we were in the hospital from August to December. As difficult as it has been to get used to the trach, it has allowed him freedoms he never before had now that he can breathe.

Over a year ago we noticed his head drops and eye rolls getting significantly worse, mind you we took him off the Keppra, but thought we were ok because we never could see the seizure. Within 10 mins of his EEG, the on-call neurologist was called and Mason is literally having thousands of seizures a day; most go without anyone noticing, but they definitely get in the way of his development.

Mason cannot walk, he cannot talk, there is a 'light' on, he recognizes people and places, knows what he wants and can communicate without words and he smiles like it's Christmas watching Mickey Mouse. He can crawl and sit on his own and pull to stand. Overall he is the most incredibly loving and strong little boy.

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NGLY1 Profile: Kaylee, age 4

Patient: Kaylee, age 4

Parents: Kelsey and Daniel

Sibling(s): Justin, age 2

Prenatal:
At about 20 weeks pregnant my OB discovered that Kaylee only had a 2 vessel chord and was a lot smaller that she should be, at the time the chord was thought to be the only reason. We monitered her very closely from that point on. At about 28 weeks I started having twice a week non stress tests (NST's) and weekly ultrasounds. Almost every time I went in for her NST's she showed little or no movement even after they would use the buzzer to try to irritate her, which resulted in ultrasounds to make sure she was ok, she always checked out in these ultrasounds. At 33 weeks she had a large ultrasound at a specialty clinic to get exact measurements and a good estimate of her weight. She had a follow up ultrasound at 37 weeks which showed that she hadn't grown at all between the two. I went to my Dr. appointment directly after that ultrasound and they admitted and induced me that afternoon. After several hours of labor they noticed Kaylee's heart rate drop with each contraction and we had to do an unplanned c-section. She was born 4 lbs 2 oz and 18 in long. Due to her size she was admitted to the NICU and stayed for 8 days. Her lungs were fully developed and she appeared healthy, their only concern at that point was her ability to eat and maintain her own body heat due to her size. She was in an incubator for several of those days and spent 2 days under the billy lights for what they considered mild jaundice. She also had an NG tube placed to help her eat. By the time she was released at 9 days old she was eating on her on and cleared as healthy.


Diagnostic journey:
  At about 10 months of age we started noticing that she was more that a little bit delayed. She was rolling over but not scooting or crawling at all. She also had been very small her whole life, but it had not been concerning because she had been growing on her own consistent curve. At this point she had stopped growing and her pediatrician started showing a lot of concern. At 11 months of age we saw her first specialist, a GI Doctor. She had recommended an NG tube and continuing to a G-tube shortly after. We had to quit Kaylee's breastfeeding cold turkey and move her to formula so we could see exactly how much she was eating. After a few days of this we discovered that she was consistently taking only about 7 oz in an entire day, which is way too little!! At this point we transferred her care to our Seattle Children's hospital so that we could have it all done in one place, and they have fantastic financial aid. We quickly scheduled her NG placement at 11 months of age because of how little she had eaten and the had dropped for about 16 lbs to about 14lbs. Her weight showed immediate improvement from the NG tube. At the time she also had blood drawn and showed elevated liver functions and low white blood counts. About a year later we placed a G tube and she is still on this today.

  Soon after seeing her GI Dr. we started seeing a biochemical geneticist and a variety of other Dr.'s. Her geneticist suspected she had a mitochondrial disorder. She was pretty quickly tested for several of the more common ones via blood tests, and had a brain MRI, muscle biopsy and liver biopsy all at one time when she was about 15-18months old (I don't remember her exact age). Her MRI and muscle biopsy were clear, but her liver biopsy showed some cirrhosis of the liver, and at the time they told us she might eventually need a liver transplant. Since then her liver functions have continued to stay about the same and they no longer believe a transplant is likely to become necessary. As well all of the blood tests we did over the next 1 1/2 years came back negative for all known mitochondrial disorders they could test for. We had discussed at about 3 years of age a whole exome sequencing test but they were having some problems requesting them and at this point her Dr. thought that anything we found out would be informational and have no treatment so we held off on the testing for a while. We did her test in April of 2013 and got her results in September (almost 4 years of age, 3 years after we began testing) which showed she had mutated NGLY1 genes which her doctor knew nothing about. He did some research and in December we were referred to Dr. Hudson Freeze and from there we were able to meet Cristina and several other families. 

    In the mean time off all the big tests we also did hearing tests which came back normal, an eye exam which showed that her sight was normal. We did swallow studies, liver ultrasounds, bone age X-rays, hip and spine X-rays and countless blood tests to continue to check her liver functions and white blood cell and platelet counts. Which were both low at some points but normalize at times. We discovered that her spleen is destroying her platelets, which we still are not sure why but believe it's because her spleen is working too hard because her liver isn't functioning properly, we have discussed the possibility of needing a stint to be placed to bipass her liver if her spleen continues to be enlarged and work too hard.


Symptoms:
Kaylee has had:
elevated liver functions
low white cell counts
low platelet counts
cirrhosis of the liver
enlarged spleen 
very low production of tears
lack of muscle tone

Physical delays:
crawls (started at about 2 yrs of age)
pulls up to stand 
takes some steps with the use of a gait trainer (walker)
Is just beginning to try to use an ipad for communication, she has no words
She has very poor fine motor skills, has difficulty with purposeful movements to complete a task
She also uses foot braces for very tight heal chords, significantly tighter in her left foot.

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NGLY1 Profile: Tim, age 3

Patient: Tim*, age 3

Parents: C and A

Sibling(s): none

"Tim" was born in June 2011 by Cesarean section at 39 weeks after fetal distress was noted.  He weighed only 2.3 kg at birth - intrauterine growth restriction (IUGR) had been noted at around 34 weeks of pregnancy and a biopsy of the placenta showed necrotic tissue. He had mild hyperbilirubinemia which did not require treatment, but otherwise his neonatal course was unremarkable and we were discharged on day three.

It was not long after that our journey began. Something seemed not right with Tim. He was crying inconsolably, not sleeping well, he moved different from other babies, he could not hold up his head very well (and he kept on nodding – we only realized much later that those nods were seizures! No doctor had picked it up). He was floppy and lying in a C-shape. He did not like to be touched or soothed. He did not like noisy environments or other people in general. He was fussy. Somehow he always managed to reach his milestones just in time in those first months and since he was feeding well, no doctor got concerned. They always sent us home with words of encouragement such as “all babies are bad sleepers” or “some boys tend to develop more slowly” but we just KNEW that something was not right!

At 6 months we took him to a neurologist and she immediately confirmed our worst fears. Our son had “brain damage” and no, there was nothing we could do but try to ease the symptoms and carry on with our lives. We were devastated! We got Tim admitted to a big university hospital in Germany and all sorts of tests were done. It was so scary and unreal. Many results came back slightly abnormal (one of them was for CDG which in the end happened to be a close match to NGLY1 deficiency), but it was all unspecific and we were discharged with no diagnosis and even more fear than before. We had:

• global developmental delay
• generalized poly-spike discharges in the EEG
• elevated blood lactate levels
• elevated LFTs
• delayed myelination in the MRI

Soon after, Tim’s seizures started to get worse (we are pretty sure they had been there before) we started a long journey of finding the right medication. This journey led Tim to another hospital stay of almost two months. He had myoclonic jerks of arms and legs and nodded with his head (atonic seizures). We kept close track of the frequency. What started out with 20 seizures a day went up to 200 while the doctors kept changing his meds again and again. Tim was miserable. He got worse from day to day. He could barely move anymore and stopped smiling. The doctors started telling us that “this was the nature of his progressive disease”. A second MRI showed his brain was shrinking. It was horrifying.

Somehow, for lack of a better idea, doctors declared him to be a suspected case of mitochondrial disease. As one doctor put it “this is the only label under which we can combine the EEG and the liver findings”. We were so frustrated with these doctors and the hospital in general!

After some months we took him out of the hospital and off the meds, but we still had no diagnosis and no idea where we were headed. We started to note involuntary movements and Tim kept on getting eye infections which resulted in corneal scarring – we first blamed the high-dose steroid therapy while actually these were fundamental symptoms of his disease. He could not close his eye lids during sleep. He was severely constipated. His sleep pattern was highly pathological with hardly any deep sleep and many arousals during the night. He was constantly tired, and so were we.

On the positive side, time showed that his regression during the hospital stay was not due to his progressive disease but due to the treatment. The longer Tim was out of the hospital the more he recovered. A new MRI in spring 2013 – although still showing abnormal results like the first one – showed that Tim’s brain had re-gained its volume. We started milder interventions for treating the epilepsy like the ketogenic diet and phased meds in and out very slowly and not as abruptly as in the hospital. Still, except for Lamictal more than a dozen medications showed no effect or only negative side-effects. Lamictal helped at least a little bit with his sleep and mood. Tim’s greatest motor achievement during that time was learning to belly crawl a few months before his second birthday.

In the summer of 2013, briefly before his second birthday, I did an internet search for “ketogenic diet check up protocols” and found Cristina’s blog. I saw pics of Bertrand and immediately started reading about his symptoms. He looked and sounded so much like Tim!!! So I sent the Mights an email and received a reply the same day. We were so excited! They too thought Tim was a close match and put us in touch with their doctors. We sent his skin cells and DNA to the States and bam…a few weeks later we had a diagnosis! Tim was the first child to be only tested for NGLY 1 deficiency (and not whole exome/genome sequencing) and the 10th child to receive the diagnosis. He is the only German child so far.  

Having a diagnosis has changed everything. We are no longer alone, but are in this together with some of the most wonderful families imaginable. The exchange between the families has been tremendously helpful and I am sure will continue to be so as we are working on finding a cure. Also, based on Bertrand’s experience and because we had run out of other options we were able to convince our doctors to put Tim on Valproate for his seizures (they had not dared to do so earlier because of his suspected mitochondrial disease). It took a long while (almost 6 months and increase up to 600 mg/day), but he became seizure free. He has been seizure free for more than three months now (knock on wood). He is a changed child. He has learned to sit up, to come on his hands and knees, to feed himself, and to take supported steps during this time. He babbles the whole day, and is so much happier and calmer than before.

“Overcomingmovementdisorder.com” has changed our lives and we’ll be eternally grateful to Cristina and Matt. We want to encourage all parents to never give up the search for a diagnosis – even if there is no cure yet, it can make a huge difference in your child’s and your own quality of life!

* Name has been changed to protect privacy.

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NGLY1 Profile: Bertrand, age 6

Patient: Bertrand, age 6
Parents: Cristina and Matt
Sibling(s): Victoria and Winston (unaffected)
Bertrand was born full-term via natural delivery. His birth weight was a surprising 5 lbs. 12 oz. (an earlier ~36 week ultrasound had his birth weight estimated at 8.5 lbs). He suffered from jaundice that did not easily resolve under bililights, resulting in a 5 day NICU stay.

At approximately two weeks old, “colic” set in and Bertrand was crying at 1.5 hour intervals around the clock. (Eventually, the colic was partially attributed to acid reflux.) At about this time, we began to see an increase in his moro (startle) reflex. His pediatrician assured us that everything was fine, but Bertrand’s movements seemed increasingly odd to us. He was rolling by 4 months, but did not smile until much later. Finally at 6-months, Bertrand was referred to a developmental pediatrician.

Despite passing multiple hearing screens, you could ring a bell beside Bertrand’s head and he would not turn to find the sound. His movements were increasingly jerky/jiggly. His developmental pediatrician suspected brain damage from the early jaundice, until an MRI came back clear but his lab results came back showing elevated liver enzyme values (AST, ALT, AFP).

Bertrand at 12 months-old, mouthing and hand wringing.
These elevated liver values and the presence of substances called oligosaccharides in his urine, kicked off a 3 year quest to diagnose Bertrand. Most suspected disorders fell under the heading “errors of cellular metabolism”. In this time Bertrand accumulated an army of specialists across the US.

On top of his developmental delay and movement disorder, additional symptoms were identified, such as peripheral neuropathy, microcephaly, and non-convulsive seizures (staring episodes, falling, small jerks). Everywhere we went, we asked doctors about Bertrand’s lack of tears, but no one could give us an answer or seemed to think it was significant.

Finally, thanks to an excellent team of researchers at Duke University, Bertrand was diagnosed via whole exome sequencing as the first case of N-glycanase (NGLY1) deficiency. N-glycanase deficiency falls in the family of Congenital Disorders of Glycosylation (CDG). Two years after the initial publication describing Bertrand’s condition, there are 16 known cases worldwide.

Characteristics of N-glycanase (NGLY1) deficiency include but are not limited to: Lack of tears (alacrima/hypolacrima) Developmental delay Movement disorder Elevated liver enzymes

While there is no cure for NGLY1, and several children have passed away from the condition, there are a number of treatments that improve patient quality of life by addressing mitochondrial dysfunction (N-acetyl cysteine, coenzyme Q10, etc.). There is also hope for an impending pharmaceutical clinical trial.

Bertrand is developmentally ~9 months-old. He cannot feed himself, ambulate, use the restroom, or speak. Bertrand is in a life skills classroom. He needs daily physical, occupational, and speech therapy. Bertrand is exceptionally happy and good natured. He loves Elmo, books, water, and playing with his younger sister Victoria.

In the face of many challenges, Bertrand continues to teach and inspire everyone around him—his parents most of all. We couldn’t be more proud or happy to call him our son.

To contact us: bertrand@might.net

For more on Bertrand: http://www.overcomingmovementdisorder.com

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