NIH NGLY1 Study Experience

Bertrand with NIH study coordinators, Lynne Wolfe and Christina Lam.

In June 2014, the National Institutes of Health saw the first NGLY1 patient as part of it's CDG Protocol.  This study is a valuable instrument for understanding N-glycanase deficiency, and developing a natural history of the disorder.  The NIH is still enrolling participants.  Interested parties should contact Lynne Wolfe.

The following links provide an overview of the study experience from the patient/family perspective:

NIH Schedule

NIH Day 1

NIH Day 2

NIH Day 3

NIH Day 4

NIH Day 5

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NIH names new clinical sites in Undiagnosed Diseases Network

David Goldstein and Vandana Shashi, who headed up the team at Duke that discovered N-glycanase deficiency, will also be heading up one of the sites for the Undiagnosed Diseases Network (UDN).  The UDN is a large step forward for undiagnosed patients everywhere.  We are hopeful that many families will soon be getting answers thanks to dedicated researchers like Drs. Goldstein and Shashi.

Bethesda, Md., Tues., July 1, 2014 - The National Institutes of Health has awarded grants to six medical centers around the country to select from the most difficult-to-solve medical cases and together develop effective approaches to diagnose them. The clinical sites will conduct clinical evaluation and scientific investigation in cases that involve patients with prolonged undiagnosed conditions. Each clinical site will contribute local medical expertise to the NIH Undiagnosed Diseases Network (UDN). The network includes and is modeled after an NIH pilot program that has enrolled people with intractable medical conditions from nearly every state, the District of Columbia and seven foreign countries. The network builds on a program at the NIH Clinical Center in Bethesda, Md., that for the past six years has evaluated hundreds of patients and provided many diagnoses, often using genomic approaches, for rare conditions. 

"Newly developed methods for genome sequencing now provide us amazingly powerful approaches for deciphering the causes of rare undiagnosed conditions," said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute. "Along with robust clinical evaluations, genomics will play a central role in the UDN's mission." Dr. Green and Story Landis, Ph.D., director of the National Institute of Neurological Diseases and Stroke, co-chair the UDN working group. 

Undiagnosed diseases are conditions that even skilled physicians cannot diagnose despite extensive clinical investigation. They may not be recognized by doctors because they are rarely seen, are previously undescribed, or are rare forms of more common diseases. 

The NIH Common Fund awarded four-year grants of approximately $7.2 million (pending available funds) to each of the six medical centers around the country. James M. Anderson, M.D., Ph.D., director of the NIH Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI), announced in an NIH telebriefing that the six newly awarded sites join a clinical site already established at NIH in pursuing cutting-edge diagnoses. In addition, this past December, NIH selected Harvard Medical School as the UDN Coordinating Center for the multi-institution network. "The NIH Undiagnosed Diseases Network has the potential to transform medicine and serve as a catalyst for new discoveries," said Dr. Anderson. "It is an ideal NIH Common Fund program-the only one focused on diagnoses of rare disorders." 

The following institutions were awarded grants to establish UDN clinical sites:

• Baylor College of Medicine, Houston; Principal Investigator: Brendan H.L. Lee, M.D., Ph.D.

• Boston Children's Hospital, Brigham and Women's Hospital, and Massachusetts General Hospital, Boston; Principal Investigator: Joseph Loscalzo, M.D., Ph.D.

• Duke University, Durham, North Carolina; Principal Investigators: David B. Goldstein, Ph.D, and Vandana Shashi, M.D.

• Stanford University, Stanford, California; Principal Investigators: Euan A. Ashley, M.D., D.Phil., Jonathan Bernstein, M.D., Ph.D., and Paul Graham Fisher, M.D.

• University of California, Los Angeles; Principal Investigators: Katrina M. Dipple, M.D., Ph.D., Stanley Nelson, M.D., Eric J. Vilain, M.D., Ph.D., and Christina Palmer, C.G.C., Ph.D.

• Vanderbilt University Medical Center, Nashville; Principal Investigators: John H. Newman, M.D., and John A. Phillips, III, M.D.   

"This type of program can invigorate a medical center anywhere in the country and in the world," said William A. Gahl, M.D., Ph.D., clinical director at the National Human Genome Research Institute (NHGRI), director of the NIH-based Undiagnosed Diseases Program (UDP) and co-coordinator of the UDN working group. "Often, patients have a lot of physical complaints and no objective diagnoses. Our goal is to use the latest tools to make a diagnosis that spans the clinical, pathological and biochemical spectrum to uncover the basic genetic defect." Since 2008, the UDP has explored this fascinating area of medical research and acquired practical insights in the process of enrolling approximately 600 undiagnosed children and adults in its clinical protocols. The multidisciplinary clinical and research team diagnosed approximately 100 patients (20-25 percent of those evaluated), discovered two unknown diseases and identified 15 genes not previously associated with any other human disease. A combination of genomic and clinical analyses contributed to the diagnoses. 

By including an additional six clinical sites, the NIH UDN will both draw upon the unique expertise of new clinical research groups and cultivate opportunities for collaboration among a larger group of expert laboratory and clinical investigators. Physicians within the network will collect and share high-quality clinical and laboratory data, including genomic information, clinical observations and documentation of environmental exposures. They also will benefit from common protocols designed to improve the level of diagnosis and care for patients with undiagnosed diseases. 

 "The UDN will look at diseases across all clinical specialties using new tools and methods of analysis for the identification of new diseases," said Anastasia L. Wise, Ph.D., a program director in NHGRI's Division of Genomic Medicine and co-coordinator of the UDN working group that oversees the development and implementation of the UDN. "The network will facilitate collaboration and shared use of genomic tools among the sites." Based on the NIH UDP experience, the UDN Coordinating Center at Harvard Medical School has begun paving the way for the new UDN clinical sites to begin accepting patients. Among the coordinating efforts are the preparation of draft protocols and operating guidelines, and the definition of an initial framework of common practices across the network. The network will share systems for data collection and develop common approaches to patient selection, evaluation and diagnosis. 

Each new clinical site may have variations in handling health insurance coverage for clinical testing and care. However, no patient will be turned away from participation in the UDN based on lack of health insurance coverage. 

"We believe that there is a substantial unmet demand for the diagnoses of conditions that have perplexed skillful physicians," said Isaac Kohane, M.D., Ph.D., professor of pediatrics at Harvard Medical School and Boston Children's Hospital and principal investigator of the Coordinating Center. "We want to address inquiries from physicians and patients throughout the country who require these services and, in doing so, create a 21^st century model for diagnosis and treatment in this genomic and information-intensive era." 

UDN investigators will share genomic data from UDN patients with the research community through multiple public repositories. Network-wide data sharing will observe standards of patient privacy, confidentiality and management of health information.  

The network will start up and test its operating procedures during its first year. It will progressively expand recruitment of patients so that by the summer of 2017, the rate of admissions at each new clinical site will be about 50 patients per year. For a period this summer, referrals from clinicians on behalf of undiagnosed patients may continue to be made through the existing NIH application pipeline. 

Instructions on applying to the UDN on behalf of a patient can be found at rarediseases.info.nih.gov/undiagnosed.
For more information about the UDN, including related funding announcements, visit http://commonfund.nih.gov/Diseases/index.
These UDN clinical site awards are supported by NIH grants 1-U01HG007672-01, 1-U01HG007674-01, 1-U01HG007709-01, 1-U01HG007690-01, 1-U01HG007708-01, 1-U01HG007703-01. 

NHGRI is one of the 27 institutes and centers at the National Institutes of Health. The NHGRI Extramural Research Program supports grants for research and training and career development at sites nationwide. Additional information about NHGRI can be found at www.genome.gov.
The NIH Common Fund encourages collaboration and supports a series of exceptionally high-impact, trans-NIH programs. Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could tackle alone, but that the agency as a whole can address to make the biggest impact possible on the progress of medical research. Additional information about the NIH Common Fund can be found athttp://commonfund.nih.gov.
National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 institutes and centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Parental Might

The Might 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.  
According to the Mights, "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."

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Grace Wilsey Foundation

The Wilsey family just launched the Grace Wilsey Foundation to fund NGLY1 research and, more broadly, change the way rare diseases are researched.  Kuddos, Matt and Kristen!

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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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NIH CDG/NGLY1 Study - Now Recruiting!

Clinical and Basic Investigations into Known and Suspected Congenital Disorders of Glycosylation

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number	14-HG-0071
Sponsoring Institute	National Human Genome Research Institute (NHGRI)
Recruitment Detail	Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 1 Max Age: 80
Referral Letter Required	No
Population Exclusion(s)	None
Special Instructions	Currently Not Provided
Keywords	Natural History; Glycosylation; Genetic Disorders
Recruitment Keyword(s)	None
Condition(s)	Congenital Disorders of Glycosylation
Investigational Drug(s)	None
Investigational Device(s)	None
Intervention(s)	None
Supporting Site	National Human Genome Research Institute

Background:

- Proteins, fats, and other molecules are the body s building blocks. Many of these molecules must have sugars, or chains of sugars, attached to work properly. People with congenital disorders of glycosylation (CDGs) cannot attach these sugars or sugar chains properly. A child or adult with a CDG can have symptoms in different parts of the body, including brain, nerves, muscles, liver, and immune system. Researchers want to learn more about these diseases to understand better what is causing the problems.

Objective:

- To learn more about CDGs.

Eligibility:

- People age 1 80 with CDG or suspected to have a CDG.

Design:

-CDG participants will stay in the hospital 3 5 days. They will have:

-Medical history and physical exam. They will answer questions about their CDG.

-Blood taken several times. Their skin will be numbed, then a needle will take blood from an arm vein.

-Samples taken of their skin, urine, and maybe stool and spinal fluid.

-Photos taken of their whole body. They can wear underwear and cover their eyes.

-Brain MRI. They will lie on a table that slides in and out of a metal cylinder. The scanner makes loud knocking noises so they can wear earplugs.

-Abdomen ultrasound. Sound waves take images of the body from the outside.

-Hand/wrist X-rays for young patients. They may have a full-body X-ray.

-DEXA bone density scan. Participants will lie on a table under a scanner.

-Echocardiogram and electrocardiogram for heart activity. Pads are stuck on the skin and the electrical activity of the heart is recorded.

-Tests of hearing, thinking, motor skills, and speech.

- Children participants may have tests done under sedation if it will benefit them directly.

- CDG participants may have other procedures during their visit. They may have follow-up visits every year.

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Eligibility

INCLUSION/EXCLUSION CRITERIA:

Patients of any gender and ethnicity age 1-80 years with a suspected CDG based on biochemical tests or a confirmed CDG based on enzymatic or molecular tests will be eligible to enroll in this protocol. Patients will also be excluded if they cannot travel to the NIH due to their medical condition. Infants under age one year or under 10 kg of body weight are excluded because care is more readily provided to older infants at the Clinical Center.

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Citations:

Apweiler R, Hermjakob H, Sharon N. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta. 1999 Dec 6;1473(1):4-8.

Freeze HH. Genetic defects in the human glycome. Nat Rev Genet. 2006 Jul;7(7):537-51. Epub 2006 Jun 6. Review. Erratum in: Nat Rev Genet. 2006 Aug;7(8):660.

Hennet T. Diseases of glycosylation beyond classical congenital disorders of glycosylation. Biochim Biophys Acta. 2012 Sep;1820(9):1306-17. doi: 10.1016/j.bbagen.2012.02.001. Epub 2012 Feb 9.

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Contacts:

Principal Investigator	Referral Contact	For more information:
Christina T. Lam, M.D. National Human Genome Research Institute (NHGRI)	Lynne A. Wolfe, C.R.N.P. National Human Genome Research Institute (NHGRI) BG 10-CRC RM 3-2551 10 CENTER DR BETHESDA MD 20814 (301) 443-8577 wolfela@mail.nih.gov	Patient Recruitment and Public Liaison Office Building 61 10 Cloister Court Bethesda, Maryland 20892-4754 Toll Free: 1-800-411-1222 TTY: 301-594-9774 (local),1-866-411-1010 (toll free) Fax: 301-480-9793 prpl@mail.cc.nih.gov

Clinical Trials Number:

NCT02089789

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