NIH names new clinical sites in Undiagnosed Diseases Network

David Goldstein and Vandana Shashi, who headed up the amazing 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 fantastic 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.

N-glycanase deficiency is an official disorder.

On June 12, 2013, Bertrand and N-glycanase deficiency made it into the Online Mendelian Inheritance in Man® (OMIM). The entry for N-glycanase deficiency is #610661 and it is cross-listed with entry #615273 for Congenital Disorders of Glycosylation, Type IV.

"The OMIM is a comprehensive, authoritative compendium of human genes and genetic phenotypes that is freely available and updated daily. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 12,000 genes. OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries contain copious links to other genetics resources.

This database was initiated in the early 1960s by Dr. Victor A. McKusick as a catalog of mendelian traits and disorders, entitled Mendelian Inheritance in Man (MIM). Twelve book editions of MIM were published between 1966 and 1998. The online version, OMIM, was created in 1985 by a collaboration between the National Library of Medicine and the William H. Welch Medical Library at Johns Hopkins. It was made generally available on the internet starting in 1987. In 1995, OMIM was developed for the World Wide Web by NCBI, the National Center for Biotechnology Information.

OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, under the direction of Dr. Ada Hamosh."

Our heartfelt thanks go out to Dr. Vandana Shashi, Kelly Schoch, Dr. Anna Need, and, last but not least, Dr. David Goldstein at Duke University for making the impossible possible.  As the Mights like to say, "keep pushing!"  :)

A very different 16 months

The last few weeks, Victoria has been obsessed with a video of Bertrand's first hippotherapy session.


Almost every morning, she will scale out of her crib like a ninja (Yes, the crib is on the lowest setting and there are no bumpers, she's just ridiculous. I promise we've tried everything.), she'll run over to Bertrand's bed, climb into bed with him, snatch his iPad from the charger on the bookshelf, and we'll wake up to the sounds of this video--on repeat.

(It's cute, but trust me, the music gets old.)

We'll walk in to find both kids watching together.  You can ask Victoria where Buddy is in the video and she'll point to him on the horse.  Sometimes she'll clarify, making the baby sign, that it is baby Buddy.

It occurred to me, based on the amount of hair Bertrand had in the video (not much, like his sister), that he was about 16 months-old at the time it was taken--the same age as Victoria right now.

Wow.  What completely different 16 month experiences for each child--AND for us as parents.

I went back and read the blog posts for that month of April 2009 and cried.  It was heartrending.

There were many "firsts" that month.  Yes, it was a first for hippotherapy.  It was also the first time we took Bertrand to Duke University, and the first time we directly heard from a doctor that Bertrand's case was basically hopeless.

And here we are 3.5 years later.  In some sense not much has changed--Bertrand's condition was recently reconfirmed as untreatable and fatal.  And yet things are totally different.

For one, I'm a lot more tired and older.  :)  But now clearly words like "brain damage", "surgery", and "fatal" don't phase me as much, if at all. Heck, more than words--broken bones, hospital stays, travel across the country to see specialists, attempting to do the impossible--it's just what we do.

We deal.  Maybe it's still denial  ;)  but I prefer to think we've finally reached a kind of peace.  We're comfortable with doing what we can rather than obsessing about what we can't.

Maybe it's finally having a diagnosis?  Certainly Bertrand's fighting spirit can be credited.  I also credit a certain spunky little sister.

Often I feel like Victoria (perhaps like many 2nd kids?) is given the short shrift.  She certainly doesn't get to ride horses, go to musikgarten, get a dozen one-on-one therapy sessions a month, or even get the same one-on-one time with her parents that Bertrand did.

But somehow Victoria, the tiny force of nature, is doing just fine.  And, Bertrand?  He's doing fine too.  Both kids are making their mark on the world in their own way.  And, this mama is proud of them both, now and always. :)

Tag! We're alive.

Bertrand's new walker arrived today! He'll practice with it during therapy.

There is a lot going on.  We're starting up a fellowship through Dr. Hudson Freeze's lab at Sanford-Burnham Medical Research Institute to identify and test treatments.

More potential cases of N-glycanase deficiency have been identified and are currently being tested at Duke University.

One of the cases is a 13 month-old boy.  Learning about this little baby, I've grown even more desperate to find a treatment.  In my mind's eye, this is who I see:




We must find a treatment.

Is your child undiagnosed?

8 month-old baby Bertrand.
Extreme cuteness may also be a symptom.

Since the identification of Bertrand's NGLY1 mutations, researchers are hoping to find/test previously undiagnosed children for the same condition.

A potential N-glycanase enzyme treatment has been identified.

I need help finding undiagnosed kids fitting this profile. Matching kids may be eligible to receive a test for this newly discovered genetic (NGLY1) disorder.

The salient features are:

• Developmental delays
• Involuntary movements starting in infancy
• Liver dysfunction detected in infancy- elevated transminases and AFP, all normalized at this time
• Myoclonic seizures starting in infancy
• Lack of tears

The presentation of kids with NGLY1 mutations may vary with severity.  Both Bertrand's mutations are located toward the end of the gene, so he may actually be one of the less affected.

The undiagnosed children may have been extensively tested for congenital disorders of glycosylation and lysosomal storage disorders, returning normal results.

Thanks for any help you can provide!

The first article citing Bertrand's genetic condition was just published in the Journal of Medical Genetics!  Our family (Bertrand, Cristina, and Matt) comprises Trio 2.  This article (PDF) was published under the Creative Commons License, so please spread the word about this fantastic study.  :)

Clinical application of exome sequencing in undiagnosed genetic conditions

1. Anna C Need1, 
2. Vandana Shashi2, 
3. Yuki Hitomi1, 
4. Kelly Schoch2, 
5. Kevin V Shianna1,
6. Marie T McDonald2, 
7. Miriam H Meisler3, 
8. David B Goldstein1,4

+Author Affiliations

1. ¹Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
2. ²Department of Pediatrics, Section of Medical Genetics, Duke University, Durham, North Carolina, USA
3. ³Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
4. ⁴Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA

1. Correspondence toDr David Goldstein, Center for Human Genome Variation, Duke University School of Medicine, Box 91009, Durham, NC 27708, USA; d.goldstein@duke.edu

1. Contributors AN: study design, data analysis and interpretation and manuscript writing. VS: patient recruitment and counselling, clinical follow-up, study design, data interpretation and manuscript writing. YH: laboratory follow-up of candidate variants, data interpretation, manuscript writing and figures. KSchoch: patient recruitment and counselling, clinical follow-up, data interpretation and manuscript writing. KShianna: sample preparation, genotyping and genotyping quality control and manuscript writing. MHM: data interpretation, figures and writing. DBG: study design, data interpretation and manuscript writing. MTM: patient selection.

• Received 10 February 2012
• Revised 14 March 2012
• Accepted 2 April 2012
• Published Online First 11 May 2012

Abstract

Background There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations.

Methods The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met.

Results This undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study,EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features).

Conclusions This study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ andhttp://creativecommons.org/licenses/by-nc/2.0/legalcode.