Vol. Xlll - July 2021 | Email Us | CDGCARE.org
In this Issue
  • CDG Education & Resources
  • Emmett's Legacy Fund Awards
  • FCDGC Research Updates
  • Working Globally to Advance CDGs
  • 2022 CDG/NGLY1 Scientific & Family Conference
CDG Education and Resources All Year Long!
Upcoming Webinar Series Broadcast
In a recent survey among our CDG/NGLY1 Family Support Network members, the highest ranked PATIENT/CAREGIVER educational program desired by our Community is: "Research Education: Process, Current Studies and Future Outlook". CDG CARE is excited to offer the AIRING of the previously recorded, 2-hour educational program - "The ABCs of Clinical Trial for the CDG/NGLY1 Community" next week! This event will be aired at SIX different broadcast times from July 26 - July 31, 2021. Pre-registration is not required, just visit our WEBINAR PAGE to view the schedule and select CLICK TO WATCH! to tune in during the most convenient broadcast time for you!

NGLY1 Resources
CDG CARE gratefully acknowledges the work of the National Organization for Rare Disorders (NORD) and Dr. Christina Lam at Seattle Children's Hospital for collaborating to develop an important new Awareness and Education piece specifically focused on NGLY1 Deficiency. To learn more, access these resources and a short educational video CLICK HERE.

Family Support Network Update
The CDG CARE Family Support Network (FSN) has already grown to over 220 members! Together we are collecting data, connecting families, standing united and advancing resources, advocacy and research for all CDGs. The Family Support Network is the most extensive membership group of global families ready to assist each other. To view our membership map CLICK HERE. And to join the FSN and start receiving our members-only newsletter (The Network News), which includes invitations to our FSN Community Meet-ups, fill out the short registration form by CLICKING HERE TODAY!

CDG CARE Awards Research Grant
CDG CARE is honored to announce that donor support has enabled us to fund a $50,000 research grant to Greenwood Genetic Center (GGC) which will use zebrafish models of CDG to investigate the mechanism of a new drug, Epalrestat, to treat PMM2-CDG. To learn more about the growth of CDG CARE and importance of Community to CDG CARE’s President and Founder, Andrea Miller, you can download the full GGC Summer 2021 Newsletter, by CLICKING HERE.

Calling all CDG Patients, Caregivers & Medical Professionals
We need your help! The 2nd phase of the "CDG Patient Journey Mapping" survey is part of an international study that aims to capture the full picture of people living with CDG. The survey is available until August 31, 2021 and is offered in 4 languages: Portuguese, English, Spanish and Italian. More information about the survey and the links to participate can be accessed HERE.

Global CDG Awareness, Education and Research Campaign
CDG CARE was honored to participate in a collaborative opportunity with Rare Revolution Magazine to share educational content, personal stories, and support on the topic of CDGs in their digital spotlight partnership with the World CDG Organization and CDG patients, professionals, advocates and associations around the globe. To access the full listing of contributions made for this unique and inspiring rare series CLICK HERE.
Emmett's Legacy Fund helps families around the world obtain much needed medical equipment
We are delighted to share that the inaugural launch of our new medical equipment grant program, Emmett's Legacy Fund, has provided much needed medical equipment and support to seven families located throughout the USA, Canada, Mexico, Brazil and Romania!

Life with CDG is tough. We understand the many challenges (expected and unexpected) that arise on a daily basis, and our aim is to alleviate some of these hardships. It is with great honor that we have been able to support medical equipment items ranging from an AAC communication device, to bath & shower seats, to a medical safety bed, a precursory grillo trainer, proper postural seating support, and even an adaptive tricycle.

Through Emmett’s Legacy Fund, we hope to help improve the quality of life and activities for individuals diagnosed with CDG/NGLY1 and their families. We will be sharing additional details on the specific items that have been supported in our new Emmett's Legacy Fund social media series which will launch on the CDG CARE Facebook Page very soon!
Emmett's Legacy Fund was created to remember and honor the life of Emmett, who was born in April 2016 with PIGA-CDG, a rare and devastating genetic metabolic disorder. Emmett was loved by everyone around him and fought through multiple illnesses and hospitalizations during the course of his short life. In February 2020, Emmett lost his battle with PIGA-CDG, but his memory lives on and continues to inspire friends and families who followed his story. Emmett's parents created this fund as a celebration of his life, and as a way to make a meaningful impact in the lives of other children diagnosed with CDG & NGLY1-deficiency.

The next round of Emmett's Legacy Fund applications will be available in early 2022. To learn more about Emmett and his life, visit www.lifebyemmett.com and for additional information about PIGA-CDG, please visit www.PIGA-CDG.org.
News from the FCDGC
Acetazolamide Clinical Trial
FCDGC/CDG CARE’s Acetazolamide Clinical Trial is well underway with enrollment. Currently there are 14 patients enrolled to the study, out of 26 available slots. Patients are diagnosed with PMM2-CDG, 4 years of age or older, and have clinical symptoms that involve ataxia. Patients are randomly assigned to placebo or treatment arms for 6 months, then are given the opportunity to extend their treatment on acetazolamide treatment for an additional 18 months. If you are interested, please contact one of the clinical centers performing this trial. Participating clinical sites include Seattle Children’s Hospital, Children’s Hospital of Philadelphia, and Mayo Clinic. Additional study information and contact information can be found on clinicaltrials.gov under the study number, NCT04679389. https://clinicaltrials.gov/ct2/show/NCT04679389 

Natural History Research Study
The natural history research study is still underway. About 150 patients have been enrolled into this study and enrollment has opened at multiple sites across the country. Participation involves annual visits with a designated healthcare provider for disease follow-up, questionnaires, and optional sample collections. If you would be interested in learning more, please contact one of the clinical sites, found here: https://www.rarediseasesnetwork.org/fcdgc/sites
New Publications
FCDGC investigators participated in a publication about D-galactose treatment monitoring for PGM1-CDG patients. The full article can be found here: https://doi.org/10.1002/jimd.12406
FCDGC investigators participated in a publication which identified a new type of CDG, EDEM3-CDG. The full article speaking to the new discovery can be found here: https://doi.org/10.1016/j.ajhg.2021.05.010
FCDGC investigators participated in a publication which describes a new genetic syndrome due to PGM2L1 deficiency, a gene highly expressed in the brain. The full article can be found here: https://doi.org/10.1016/j.ajhg.2021.04.017
Other News
FCDGC investigators attended the 2021 Scientific CDG Symposium on June 23-24th, which took place virtually. The event was coordinated by KU Leuven in Belgium. Members of FCDGC presented on a variety of topics with other members of the international CDG scientific community.

Social Media Presence
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Glycomine's Natural History Study Informs Potentially Lifesaving Update to Standard of Care
for PMM2-CDG Patients 
Glycomine, Inc., a biotechnology company focused on developing new therapies for orphan diseases, announces the publication in Molecular Genetics and Metabolism of a key finding from a natural history study of phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG). In this study, the levels of morning cortisol and adrenocorticotropic hormone (ACTH) were measured in a cohort of patients and found to be significantly below normal, indicating PMM2-CDG patients are at risk for secondary adrenal insufficiency. These data provide key insights to improve standard of care, as early recognition of adrenal insufficiency and initiation of glucocorticoid replacement therapy and stress dosing could be lifesaving. The authors conclude that morning cortisol and ACTH levels should be evaluated at least annually for all patients with PMM2-CDG. If abnormal, a low dose ACTH stimulation test should follow to evaluate the hypothalamus, pituitary, adrenal (HPA) axis. The research entitled, “Should patients with Phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency?” is available at this link: https://doi.org/10.1016/j.ymgme.2021.06.003.

“Endocrinopathies in PMM2-CDG have not received the attention they deserve, especially considering that glycoproteins are involved in virtually every endocrine axis,” said Kyriakie Sarafoglou, M.D., Associate Professor in the Department of Pediatrics at University of Minnesota and lead author of the paper. “Through an international collaboration, this study was the first to identify that patients with PMM2-CDG are at risk for secondary adrenal insufficiency and to suggest that morning cortisol and ACTH monitoring should become part of standard care in these patients.” 

The natural history study completed enrollment with 139 PMM2-CDG patients at 11 sites around the world (ClinicalTrials.gov Identifier: NCT03173300). “We initiated this natural history study, which is the largest longitudinal study ever undertaken for this disease, to learn more about how PMM2-CDG affects patients and inform the design of our clinical trials for GLM101,” said Horacio Plotkin, M.D., FAAP, Chief Medical Officer of Glycomine. “Through thoughtfully and scientifically studying the clinical presentation and biochemistry of PMM2-CDG, our investigators have uncovered a significant risk factor that is often masked by other co-morbidities of the disease. We thank the investigators and the patients and families who participated in this study for their time and support as we advance into clinical trials GLM101. Good things happen when patients and families, investigators, and companies work together.” So read the full press release, click HERE.
Another genetic cause of CDG identified:
By Andrew Edmondson, MD, PhD

FCDGC investigators continue to increase the number of genes associated with CDG. There are approximately 700 genes in the human genome related to glycosylation and over 150 of them have been associated with CDG to date. In a recently published report in American Journal of Human Genetics, FCDGC investigators identified another CDG associated with biallelic mutations in EDEM3. FCDGC reported 7 families composed of 12 EDEM3-CDG individuals. Affected individuals typically have developmental delay particularly affecting speech, behavioral disturbances primarily consisting of hyperactivity, attention deficit, and anxiety, and about ¼ of EDEM3-CDG individuals have failure to thrive and require a G-tube. EDEM3-CDG is an N-glycoslyation disorder with normal transferrin analysis, but with global abnormal glycosylation detectable on N-glycan analysis. This new CDG was reported at the 5th Annual World CDG conference and the 2021 CDG Scientific Conference.

The report is titled “Bi-allelic variants in the ER quality control mannosidase gene EDEM3 cause a congenital disorder of glycosylation” and is available here: https://authors.elsevier.com/c/1dFuAgeW~iVO

FCDGC Natural History Study:
A Focus on GPI Anchor Disorders
The FCDGC Natural History is instrumental in improving our understanding of what happens as children with CDG grow up. Recently, FCDGC investigators teamed up with an international effort to better understand the GPI anchor disorder, PIGT-CDG. With this study, 49 individuals with PIGT-CDG have been reported in the medical literature. This study found that individuals with the c.1582G>A; p.Val528Met or the c.1580A > G; p.Asn527Ser variant have more mild symptoms compared with other PIGT-CDG individuals, and individuals with both variants or two copies of these variants were even more mildly affected. The more mild PIGT-CDG individuals tend to have moderate to severe developmental delay, later onset of seizures, and are more often able to become seizure-free with only one anti-epileptic medication. More severe PIGT-CDG individuals have profound developmental delay, focal epilepsy that was resistant to medication therapy, and risk of premature death. The study provides some early insights in the potential natural history in adulthood and is important for caregivers and healthcare professionals preparing for later onset disease manifestations and when counseling families with infants newly diagnosed with PIGT-CDG, particularly when they have milder genetic variants. The study report is titled “Deep-Phenotyping the Less Severe Spectrum of PIGT Deficiency and Linking the Gene to Myoclonic Atonic Seizures” and is available at: https://www.frontiersin.org/articles/10.3389/fgene.2021.663643/full

We want to thank all the families who are currently participating in this now international study. We anticipate that the coming years will provide us with many additional important insights that will improve the care of all CDG patients. The FCDGC Natural History study is accessible at 10 US sites. If you are interested in joining, see the FCDGC website for contact details of the study site nearest you: https://www.rarediseasesnetwork.org/fcdgc/sites.
Cure SRD5A3 Research & Resources Update
CDG CARE is delighted to share the following exciting research and resource updates from our friends at Cure SRD5A3! You can also keep up to date and follow Cure SRD5A3 on their website: Welcome to Cure SRD5A3 - Cure SRD5A3

Gene therapy 
Here at Cure SRD5A3, we are nearing completion of the first mouse efficacy study with the Gray lab at UTSW. We are analyzing the treated mice for behavior improvements, expression of the gene therapy in the brain, immune response and toxicity.  We are currently working on characterizing the behavior of this SRD5A3 mouse model more extensively before we begin a second efficacy study! The second study will be using a different method to administer the gene therapy that is expected to increase expression of the therapy in the brain. 

Drug repurposing 
We also carried out a drug repurposing screen in worms with Modelis and identified ~70 drug candidates!  We are now working to narrow down this list by evaluating these candidates for their ability to improve glycosylation and increase dolichol/decrease polyprenol levels in patient-derived fibroblasts.

Biomarker discovery 
Biomarkers can be used to help diagnose a disease and evaluate how well a drug is working  in clinical trials.  We are currently working to launch a biomarker discovery project  for SRD5A3-CDG this year! Stay tuned for more details and information on how to participate in this exciting research! 

Research models to study eye symptoms 
A structure of the eye called the retina is often affected in SRD5A3-CDG which can lead to vision problems. We are working to launch several projects focused on generating new research models to study this feature of SRD5A3! This will likely include a new mouse model and retinal cell models generated from iPSCs . Establishing good research models is an important step towards testing potential eye therapies in the future.

New Resource for SRD5A3-CDG
We have recently developed a new educational report on SRD5A3-CDG and our ongoing research. This content has specifically been developed for patients & their families and for researchers & healthcare professionals. In this report, you will learn more about: signs, symptoms & diagnosis; how glycosylation is affected in SRD5A3-CDG; research models & potential therapeutic approaches; current & future research studies at Cure SR5DA3; and so much more! Read the report & let us know what you think!
CDGs don't have borders. Why should we?
By Ivan Martínez-Duncker MD ScD

It is a fact that CDGs have no borders and our efforts to tackle these diseases requires us a global responsibility to increase awareness, diagnosis, therapy, and research in benefit of CDG patients and their families. It is reasonable to assume that in most parts of the world CDGs are not being diagnosed or that diagnosis is attained too late. It is even very possible that diagnosis does not change the clinical outcome of patients as health systems lack a solid public policy regarding management of rare diseases and even less so of CDGs. Also, a grave underfunding of science complicates the frequently needed partnership with research institutions that accompanies CDG diagnosis and treatment, particularly in cases where new mutations or affected genes are found.

I consider that it is urgent for the handful of consolidated networks of CDG scientists, physicians and families that have sprung in Canada, the United States and Europe to develop a joint global strategy to share their knowledge and strength, to know who are the physicians and scientists working on CDGs in every country, to know the CDG families that are fighting for better healthcare and to give them hope and guidance so they don’t have to suffer the learning curves of networking and even benefit from joint funding and clinical trials. It is also important for these consolidated networks to get to know the cultural and economic differences that many times avoid transferring knowledge from a highly developed country to an underdeveloped one. We frequently say in Mexico that USA or European strategies do not work, not because they are not good strategies but because they cannot work here (culture, poverty, corruption, deficient health systems, etc.), but if we find out how to adapt them to the local challenges then we can make them work very well. We call this adaptation “Tropicalization”. So, networks also must be sensitive to local challenges because the advice/support we give to others, may not be the best, particularly if they live in different and very challenging circumstances.

To network between countries must be seen as a synergistic activity that not only shares knowledge and funds with those that are more vulnerable, but also increases global data on CDGs that are of benefit to everyone, to both scientists and families and ranging from basic science to multi-national clinical trials. I believe that we require a global CDG strategy and that we are ready to bring it forward as a very powerful instrument to empower everybody to push the political agenda in their countries and beyond them.

In Mexico, it was not until 2014 that the first cases of CDG were reported by our lab, two children with ATP6V0A2-CDG. In 2020 we reported the first PMM2-CDG case in Mexico and recently a Latino pathogenic variant involved in a case of PMM2-CDG. Also, in the next weeks we will be reporting the first ALG1-CDG case reported in Latin America involving a novel pathogenic variant. The reported data benefit Mexicans but also all the CDG communities around the world, this is an idea we must continue pushing forward. I believe that there is a lot of high value knowledge that we are not gathering from CDG patients, particularly because they are not being diagnosed or reported. I am afraid to say that the number of undiagnosed CDG patients is very certainly far larger than the diagnosed ones - let us change that - but to do so, we must act globally and with a high level of coordination.

A great partner in our efforts in Mexico to develop a local network is CDGMéxico, a recently created CDG family organization created by Mariana and Paul, parents of Romeo that has PIGA-CDG. You can specifically read more about Romeo's parents story and A Carer's Perspective in a recent global campaign to raise CDG awareness and education here: https://www.rarerevolutionmagazine.com/blog/a-carers-perspective-the-impact-a-diagnosis-of-congenital-disorders-of-glycosylation-cdg-has-on-a-family.

Do not hesitate in contacting CDGMéxico so that your knowledge and strength go beyond the borders, CDG patients, and their families deserve it so much, and we are stronger together.
Save the Date!
Celebrate Rare! Celebrate CDG!
Mark Your Calendars...

CDG CARE is excited to invite our CDG & NGLY1 medical professionals and families to the upcoming, in person, CDG/NGLY1 Scientific & Family Conference, February 25 – 27, 2022!

This event, "CDG Models and Therapy", is being organized by CDG CARE in partnership with Sanford Burnham Prebys and will be held at The Dana Hotel on Mission Bay in the beautiful city of San Diego, California.

Visit our EVENT PAGE to access the most current conference information, sponsorship opportunities, preview the tentative agenda (coming soon!), learn about family scholarship opportunities, and find out how and when you can register to join us for this collaborative educational opportunity!