About
What is CDG?
First described by Dr. Jaak Jaeken in 1980, Congenital Disorders of Glycosylation (CDG) are a rare group of genetic disorders that result in faulty glycosylation. Glycosylation is the cellular process of adding sugar chains to proteins by means of enzymes and this pathway is necessary for the normal growth and function of cells, tissues, and organs. Traditionally there have been two types of CDG recognized (type I & type II). The newer deglycosylation disorder (NGLY-1) is now also recognized. (see NGLY-1 New Yorker article.) Approximately 1000 individuals worldwide have been diagnosed with CDG type I. To date, twenty-five subtypes of CDG-I have been identified. Ten children have now been diagnosed with subtype CDG-1L (ALG9-CDG). Maria is one of them. Features common to most CDG subtypes are failure to thrive, developmental delay, hypotonia, and seizures. Some subtypes have more unique characteristics such as liver disease, clotting disorders, or cystic kidneys.
To learn more about CDG, please visit the CDG Care website: https://cdgcare.org/what-is-cdg/
What is the FoG?
Dr. Russell Webster served as the Head of the Department of Obstetrics in Saint John, New Brunswick from 1978 to 1999. He was a skilled surgeon and an exceptional clinician, having welcomed thousands of newborns into this world. When his granddaughter, Maria, was born in September 2006, he sensed that there was something unusual. Although her first few weeks of life seemed routine, he noted unusual eye movements and began to suspect that all was not well. It was months later that Maria was diagnosed with ALG9-CDG.
In January 2011, Maria's father, a medical microbiologist, attended the fourth annual International Meeting on CDG in Leuven, Belgium. Here he learned about diagnostic testing for CDG and the relevant cellular pathways. Maria's father was encouraged by the advancements that have been made by researchers who
were present at the conference. However, there were many ongoing studies pertaining to the most common CDG subtypes but far less research being conducted on rarer subtypes, like Maria's ALG9-CDG enzyme deficiency. Additionally, it is generally suspected that CDG is underdiagnosed in children. Given this, Maria's grandfather and family established Foundation Glycosylation (the FoG), with assistance from the Saint John Regional Hospital Foundation. Dr. Russell Webster was grateful to have the support of his local medical community. His years of service and dedication to his community were recognized by his colleagues who provided both moral and financial support to help get the Foundation off the ground in 2011. Since that time, the FoG has supported CDG research, raised awareness of the disorder, and advocated for individuals who have these rare enzyme deficiencies.
Foundation Glycosylation research initiatives have been welcomed by local researchers at the University of New Brunswick and Dalhousie Medical School. Furthermore, well established CDG investigators in the United States and Europe have embraced the opportunity for collaborative research projects. Glycosylation is an essential process for normal human function. A greater understanding of glycosylation can have an impact in many areas of biology -- including immunology, infectious diseases, hepatology, and opthalmology -- and improve the lives of children and their families who are impacted by CDG and related enzymatic disorders.
Mollie McGuire was hired by the FoG to work as a student intern. During her time with the FoG she published an article in the Dalhousie Medical Alumni Association magazine VoxMeDal. The article, posted below, outlines the FoG initiative and the collaborative research being guided by Dr. Thomas Pulinilkunnil and Dr. Petra Kienesberger. (McGuire, Mollie. 2014. A Labor of Love for a Parent and Physician. VoxMeDAL: 34-35.)
Drs. Pulinilkunnil and Kienesberger with Maria Webster
A Labour of Love for a Parent and Physician
Dr. Duncan Webster ’01 shares his personal journey: opening avenues of collaboration to advance CDG research in Saint John and Atlantic Canada
By Mollie McGuire
Student Intern, Foundation Glycosylation
As Maria struggled through her first year of life with the extremely rare enzyme deficiency known as ALG9-CDG, I recall one day speaking with my colleague and former Dean of Medicine, Dr. Noni MacDonald. With years of experience working with children battling chronic diseases, Noni explained that as parents of sick children learn to cope with a difficult situation, they take the initial dreams that they have held for their child and they gradually set them down. Once they do that, they can begin to pick up new dreams and live more graciously and with renewed hope and happiness. This is hard to do, but over the years this is what Anita and I have done as Maria’s parents. As Maria’s father, I hope that one day she will learn to walk, and I dream that one day she will have the ability to effectively communicate. And I desperately pray that she will maintain relative health and comfort. As a physician, I see great opportunity in gaining insights into Maria’s disorder. Her condition is rare yet holds many secrets to cellular function and physiology. Through focused research, treatments may be developed for this currently untreatable condition and a deeper understanding may be gained of this essential cellular process of glycosylation that impacts all cells, as well as many directly and indirectly related disorders/
-Dr. Duncan Webster ‘01
Glycosylation is an extremely important function by which all human cells build sugar chains or glycans that are subsequently attached to other functional molecules, including proteins and lipids. The products of these attachments are called glycoproteins or glycolipids and are required for the normal growth and function of all tissues and organs. The process of glycosylation requires over 100 enzymes, each triggering separate steps in the glycosylation pathway. A malfunctioning enzyme, no matter where it falls on the pathway of glycan synthesis and metabolism, can result in a congenital disorder of glycosylation (CDG).
The specific malfunctioning enzyme determines the sub-type of CDG and the impact on the body structures and functions that may vary to a great degree.
In the past 35 years, glycobiologists have identified nearly 70 human glycosylation disorders, each with its own defective enzyme. Among the rarest type is ALG9-CDG, of which Maria Webster, the six-year-old daughter of Dr. Duncan Webster ’01, is the third in the world to be diagnosed. Maria’s CDG syndrome includes hypotonia, frequent seizures, cystic kidneys, and hepatomegaly with severe cognitive and physical developmental delays. There is currently no treatment for her disorder. As a result, Maria’s family established Foundation Glycosylation (the FoG) in 2011 to raise both awareness of the disorder and funds to support research targeting therapies for CDG. With the help of many researchers, including DMNB’s Drs. Thomas Pulinilkunnil and Petra Kienesberger, much progress has been made.
In collaboration with Dr. Webster, Dr. Kienesberger aims to investigate the mechanisms for heart function defects in CDG patients and find new ways to treat cardiac dysfunction and improve quality of life and life expectancy for CDG patients with heart disease. Dr. Pulinilkunnil, also working with Dr. Webster, aims to examine molecular pathways by which impaired glycosylation promotes intracellular distress specifically in organelles like mitochondria, endoplasmic reticulum, and lysosomes that are mainly responsible for generating energy, performing quality check on proteins, and degrading cellular waste. This collaborative research will identify and characterize novel pathways and proteins mediating pathological effects of defective glycosylation. Moreover, researchers will employ yeast and zebrafish as model organisms for addressing this research, which will help find novel therapies targeted at improving organ function in individuals with CDG. Their next goal is to validate protocols and platforms that will enable measurement of glycosylation intermediates and examine signaling pathways that link glycosylation disorders with cell and organ defects. This is a promising development that will advance CDG research in Saint John and Atlantic Canada.