The FoG is proudto be a PLATINUM SPONSOR for the upcoming Sanford Burnham Prebys Rare Disease Day Symposium & CDG Family Conference, which will be held on March 1, 2024.
For more information about the symposium, CLICK HERE.
SUMMER INTERNS' REPORT | August 2023
PIGN-CDG and CDG Diagnostics in Atlantic Canada
By Charlotte Nice and Allie Scott
Isabel Kromer lived twenty-eight years before receiving her diagnosis of a genetic disorder so rare that there have only been 22 cases reported to date. Today, we know that Isabel suffers from a rare type of congenital disorder of glycosylation (CDG), that is caused by a mutation in the PIGN gene – called PIGN-CDG. However, for almost three decades, Isabel’s parents, Elizabeth and Rob Kromer, advocated for their daughter’s array of medical conditions to be recognized for what they are – a reality that is unfortunately not so rare for many families in similar situations across the globe. Elizabeth and Rob explained it this way, “As we travelled on our journey with Isabel, what a difference it would have made for us to have had Isabel's seemingly disparate medical concerns recognized for what they were - manifestations of CDG. As it was, each of Isabel's conditions was addressed separately as we learned anything, or as she went into some kind of crisis. As parents we often had to push for diagnostics and assessments.”
Living in rural Prince Edward Island, at the age of 7 years, Isabel was diagnosed clinically with Angelman Syndrome – another genetic disorder that encompasses many of the same symptoms as some sub-types of CDG, including seizure disorders and developmental delay. Chromosomal and genetic testing were performed on Isabel to the extent available at the time, and the results were inconclusive. However, Isabel was given this provisional diagnosis of Angelman Syndrome based upon her clinical presentation, in the absence of definitive lab results. The PIGN gene, whose mutation is responsible for Isabel’s sub-type of CDG, was not discovered until 2011, meaning that any genetic testing performed prior to this would not have revealed that what Isabel was actually suffering from was PIGN-CDG. Since the discovery of the PIGN gene and its link to PIGN-CDG, there have been just 22 reported cases globally, and Isabel Kromer is by far the oldest.
The late discovery of the PIGN gene, made for a long and difficult road for the Kromer family, toward a proper diagnosis for Isabel. In speaking with Elizabeth and Rob Kromer, they shared details on their tumultuous medical journey with their daughter. “Our determination to see Isabel’s unique medical situation identified if possible, was often sadly met with direct opposition. Several physicians didn’t recognize her extreme medical fragility, and openly expressed that the problem lay with us, rather than with Isabel, in that we couldn’t handle having a child with Isabel’s disabilities.”
The Kromers often encountered medical professionals who had no desire to pursue Isabel’s case, due to how challenging it was to come to a clear diagnosis. For decades, the Kromers travelled across Canada and the United States for consultations with specialists and to undergo further testing, in hope of finding answers.
It was when a new neurologist took over Isabel’s care just a few years ago, that further testing led to a proper diagnosis. At their initial meeting with this doctor, they discussed Isabel’s medical history in depth, and recalled all of the years of testing she had undergone. This was when it was suggested that the Kromers pursue further genetic testing for Isabel, because of the drastic strides that had been made in the field of genetics over the past 20 years. The Kromers gladly took this suggestion and began working with the Maritime Medical Genetics Service (MMGS) at the IWK Children’s Hospital in Halifax, Nova Scotia. After a refined search, the Genetics Team had narrowed the possibilities down to 285 rare genetic disorders that they believed could account for Isabel’s condition. After seeking permission from the Kromer’s to pursue Isabel’s case further, state-of-the-art genetic analysis was performed at a lab in Finland, and her diagnosis of PIGN-CDG followed.
For Isabel’s parents, having a clear diagnosis makes an incredible difference, as it gives them the ability to continue to pursue their daughter’s unique medical condition in a much more focused, and directed way. They are also hopeful that Isabel’s diagnosis will provide guidance for those facing similar struggles, and perhaps lead the way toward further research on PIGN-CDG. Ideally, Isabel’s long and difficult journey, and advances in genetic testing, may prevent another family from waiting three decades for an accurate diagnosis.
The COVID-19 pandemic was unnerving for everyone, but especially for individuals living with a weakened immune system. Elizabeth and Rob note that they have navigated the COVID-19 pandemic successfully. “When in doubt, we have erred on the side of caution, as Isabel is severely immunocompromised. Isabel is up to date on all of the recommended COVID-19 vaccines for someone who is immunocompromised.
As restrictions have been lifted at this time, Rob and Elizabeth say they are once again getting back to outings with Isabel. The Kromer family is enjoying the family outings, mentioning that Isabel is a very sociable person, and she loves to shop.
Isabel celebrated her 32nd birthday in November of 2022. Elizabeth and Rob explain that Isabel's seizures have been less frequent over the past few years with medication changes and adjustments. They are grateful for their daughter’s diminished seizure response, and they are hopeful this will last.
For over two decades, doctors have diagnosed CDGs based on specific symptoms and limited screening tools, but the severity and prognosis can vary greatly depending upon the specific type of CDG. Specific symptoms and their severity can vary among individuals with the same CDG type and even among affected individuals within the same family. Because most types of CDG have only been reported among a handful of individuals and the number of types of CDG continues to expand, it is difficult for doctors to develop an accurate picture of associated symptoms and prognosis. Many of the symptoms of CDG are similar to those of other conditions, and patients with CDG are often misdiagnosed initially with different disorders, as was the case with Isabel.
It is now recognized that CDGs should be considered as a possible diagnosis whenever a person has unexplained symptoms affecting multiple body systems or when a single health problem cannot be otherwise explained. Because many CDG types have only recently been identified, and because so many are rare, it is thought that many people with CDG may remain undiagnosed or misdiagnosed. It is not an overstatement to say that having an accurate diagnosis can change the story for an individual and family impacted by a rare disorder.
Lab-based diagnostics for CDG begins with a highly sensitive serum transferring iso-electric focusing assay to screen for abnormal glycosylation. With a blood sample, this test can screen for most CDGs. The transferrin assay is positive in about 60% of CDG diagnoses, however,can show normal results with certain sub-types of CDGs. Therefore, further testing may be required to accurately screen and then diagnose an individual with CDG. To complement the transferrin assay, DNA sequencing-based testing can be used to confirm a diagnosis and to identify the specific type and sub-type of CDG. Confirmatory testing often involves genetic testing called next generation sequencing (NGS). For a full description on the CDG diagnostic process, visit https://www.cdghub.com/about/#diagnosis5 .
Genetic testing has been part of medical practice since the early 1990’s. Sequencing enables doctors with the ability to search for mutations that cause known disorders, such as Isabel’s. With a single test, NGS allows for analysis of all the genes known to be associated with CDG, and this analysis can pinpoint the specific CDG sub-type. Having a coordinated approach to testing and diagnosis means that the path to analysis with a confirmatory result is more efficient and accurate. This technology can also help to identify other new and previously undiagnosed CDGs.
At the time of Isabel's birth, CDG was a newly discovered genetic disorder. The diagnostic tools that exist today were not available, making a diagnosis of CDG extremely difficult. Even today, diagnosing CDG can be difficult as there is a lack of simple screening methods for many CDG sub-types, as well as a lack of awareness and information regarding CDGs in the medical community.
We hope that establishing comprehensive testing for CDGs in Canada will help to develop a more accessible and robust diagnostic path that will allow doctors to provide a timely diagnosis. Our goal is that in the near future, this unique opportunity will be used as a catalyst to bring together experts from different medical and scientific fields in an effort to accelerate the discovery of treatments and build a stronger CDG community in Canada and around the globe.
Saint John Regional Hospital Foundation
Level One, Saint John Regional Hospital
400 University Avenue
P.O. Box 2100
Saint John, New Brunswick, Canada
The FoG, a local not-for-profit, supports research on the development of therapies targeting Congenital Disorders of Glycosylation (CDG), helps raise awareness of the disorder, and advocates for individuals living with these rare enzyme deficiencies.