Anyone who observes Dr. Kishnani with her patients and their families will understand her passion for and dedication to treating Pompe Disease. An award-winning and globally acknowledged expert in the field, she collaborates with the equally dedicated Erin Huggins to further our understanding of Pompe and improve the health and well-being of those affected.
They joined us for our latest "Ask the Expert" interview with Baebies Product Manager, Jon Washburn. Discover their recent insights on Late Onset Pompe Disease, including symptom age of onset, variants of uncertain significance, and how to approach clinical diagnosis
Read their discussion below...
Over the last 10 years, what has been most surprising to you in your experience identifying and treating Pompe Disease?Jon
The single largest surprise has been the frequency of Pompe disease. It's changed from approximately one in 40,000 to anywhere from one in 10,000 to one in 20,000, mostly due to the increase in cases identified on newborn screening.
But I would say also one of the biggest surprises for me has been this phenotype that likely has been overlooked for Late Onset Pompe Disease (LOPD) and how early it can present.
When we look at babies with LOPD, we are finding features that are common in older children and adults with Pompe. We are seeing subtle features in children that normally might not be obvious until 10 or 20 years of age rather than at a few months of age. Historically, we felt that a baby presenting with LOPD symptoms would be the exception, but this seems less likely as we continue to learn more.
It's been quite eye opening for all of us that this is a whole new emergence of understanding.
Erin just recently published a beautiful paper on the emerging phenotype and the understanding of the phenotype of LOPD in the newborn screening setting.
In our previous interview, you described the significance of cardiac involvement in differentiating Late Onset Pompe from Infantile Onset Pompe. What makes identification of cardiac involvement an essential piece in establishing a diagnosis of IOPD vs LOPD?Jon
I think one of the easiest aspects for Pompe, in the newborn screening setting, is if we already see evidence of cardiomegaly or cardiomyopathy or an EKG showing the biventricular hypertrophy, in the first few days of life, that child is going to get a diagnosis of IOPD and get enzyme therapy.
However it is important to know that the pediatric norms for EKG are different than for adults. So, what's being called abnormal is sometimes just a variant of normal or a structure abnormality not associated with Pompe. This is why we make the recommendation, and that's included in our paper, that ECHO and EKG be reviewed by a pediatric cardiologist.
In the late onset setting, we do not expect to see cardiac enlargement and generally the diagnosis is made based on enzyme activity and genetic testing. Symptoms are not usually obvious within the first few days or weeks of life. This can be a little bit challenging to tease out, especially for providers that haven't seen a lot of patients with LOPD.
There's been several cases that Dr. Kishnani and I have seen together where there's been an IVS mutation [a well-studied late onset variant that is considered cardioprotective], and some finding on ECHO or EKG that is not typical of Pompe disease and is most likely either unrelated or a variant of normal. However, in the setting of a positive newborn screen for Pompe, this often gets misinterpreted as IOPD and then the family receives an inaccurate diagnosis. This can result in starting treatment in children who may not need it and cause a lot of undue stress on a family.
We will sometimes get very worried phone calls from parents or providers themselves who are not really sure what to do. Like Dr. Kishnani said, a pediatric cardiologist should be involved when the findings aren’t clear or aren’t lining up with the genotype.
Some states are understandably concerned when they add Pompe to their screening panel because they appreciate how complicated it can be. When programs reach out to you, what are some key points you suggest they consider?Jon
I hope we've been able to dispel the current belief in some state newborn screening labs where they are thinking - "Who really cares LOPD?" Some even consider changing their cutoff to only capture infantile Onset Pompe (IOPD).
Babies who screen positive and do not have cardiac involvement through the first year of life, by definition, fall into LOPD. Amongst them, even in those with the common late-onset variant [IVS splice site variant] we have found evidence of muscle involvement including an increase in the biomarkers like CK [creatine kinase, a muscle enzyme] and AST [aminotransferase, a liver function enzyme that is also present in the muscle], and in physical therapy and kinematic postural abnormalities.
These are things that we have clearly missed for decades because these babies would otherwise have only presented as someone with a developmental delay, or "clumsy child," or just "not athletic," and then they come to attention much later.
It’s important to remember that in many cases, individuals with LOPD aren't diagnosed until they start showing symptoms which we know can be in early childhood and well into adulthood. When symptoms start appearing, that often triggers what is called a "diagnostic odyssey" which describes the journey it takes to get to a diagnosis. This can be over a decade long and often includes seeing multiple specialists, unnecessary and sometimes painful testing, and a financial burden on top of all that.
So a very real benefit of including LOPD in newborn screening is saving people from years and years of wondering "What's wrong with me?" and potentially a lot of time and resources.
We understand the hesitation as there can be cases where a genetic variant is unknown – called a variant of uncertain significance or a VUS. Perhaps we have never seen it before, but this does not mean the baby does not have Pompe. When we see a VUS, which will happen more and more with newborn screening, we want to know - has the baby been evaluated? Erin can speak to the many babies who have come to us from centers around the country. They're told that the child looks completely normal, and it's not the case when we are seeing them. The findings can be very subtle.
On the other hand, some families are being told their child is very sick, when they're not – but they do need evaluation.
Our paper is on is these more subtle findings that challenge the way we think about it: symptomatic versus asymptomatic patients. Is there really a clear line between those two?
Yes, we receive calls and emails from physicians in newborn screening states frequently with questions about a positive result. We know that Pompe is rare and there aren’t many specialists, even geneticists, with a lot of experience in the condition so we always are happy to provide our input.
I think in order to avoid either under-diagnosing or over-diagnosing Pompe, it’s really important that we continue to spread the word on the work we are doing and to provide education to physicians, including geneticists and pediatricians, as well as newborn screening labs. If we are going to screen for Pompe, it’s really important that we have a deep understanding of all aspects, even the farthest ends of the spectrum, which is what we aim to accomplish in our research.
Do you recommend a difference in management between what variants are suspicious of causing late onset Pompe versus those of uncertain significance?Jon
It’s tricky with LOPD because the criteria for what is considered an “affected” patient is not yet clearly defined, and like we have said, the signs can be very subtle. Most of the time, these symptoms aren’t apparent within the first month of life, which is when newborn screening results that include genetic testing are coming back. It’s important to understand that we might not get a clear answer right away, especially in the setting of a VUS.
As we have said before, it is very important that the child is evaluated, possibly once a month or every few months until we have a clearer understanding. We understand how stressful this can be for parents, so clear communication between patient and provider is very important.
I think our complication comes in, and Erin can speak to this, sometimes you've got an unusual combination of genetic variants. This can be VUS on one allele plus a pseudodeficiency variant or, a VUS and pseudodeficiency on the same allele PLUS a known mutation such as the IVS. That's when we get tripped up. What do you do with this information?
- Is this VUS really contributing?
- Is it the variant resulting in low enzyme activity?
- Or is the pseudo deficiency contributing to it?
Those become a little more challenging. So, it becomes a counseling issue for families, right?
What steps have you taken, and continue to take, to investigate the effects of variants of uncertain significance?Jon
Right. This is when it becomes very important to test the parents, to understand what each variant is doing on its own. Genetic counseling for these families is essential so they understand the diagnosis and the next steps they will face, both immediately and throughout their child’s lifetime.
Besides the immediate concerns for their baby, families want to know – will I have another child with Pompe? Could I actually have Pompe? It suddenly goes beyond the positive newborn screen and affects entire families. We have had families that end up with one or two more children diagnosed with LOPD after their baby had a positive newborn screen, because the other children were born before Pompe was added to their states panel or they were born in a different state. This is why we are really motivated to learn how to interpret these rare and uncertain variants.
To Erin's point, when we speak with some of the families, some parents also talk about a concern for fatigue or pain, or some muscle symptoms and they're often told that, “oh, you're a carrier.”
In those scenarios, we have done enzyme testing, not just targeted sequencing or targeted mutation analysis. We have actually identified, in a couple of IOPD families, parents who are affected with LOPD.
What is your most important advice for Newborn Screening Programs as they start and establish their own follow-up protocols for Pompe?Jon
First, I think Erin and I both would say working as a team approach, getting good physical therapists and getting a pediatric cardiologist. I think those would be two very important aspects.
Second, the importance of very, very early intervention in terms of treatment for infantile onset Pompe. Definitive treatment with enzyme therapy for infantile is critical, even a few days makes a difference.
Third, do not be dismissive of, someone that's considered as late onset. That is very important. Children with late onset should still be followed closely and monitored for symptoms of disease onset and progression, even if symptoms are subtle.
- Video: How to Stay (True) Positive
- IOPD vs LOPD: Baebies Interview with Dr. Priya Kishnani
- Publication, Huggins, et. al.: Early clinical phenotype of late onset Pompe disease: Lessons learned from newborn screening
Our Pompe Experts:
Priya Kishnani, MD, MBBS
Dr. Kishnani is the Chen Family Professor of Pediatrics, chief of the Division of Medical Genetics at Duke University Medical Center as well as medical director of the YT and Alice Chen Pediatrics Genetics and Genomics Center. Dr. Kishnani moved to the United States in 1991, after completing a residency in pediatrics in Mumbai, India. She went on to do a second residency in pediatrics as well as a fellowship in genetics and metabolism at Duke University Medical Center. Shortly after, she joined the faculty at Duke University. Dr. Kishnani is certified by the American Board of Medical Genetics and the American Board of Biochemical Genetics. She also serves as the director of the Lysosomal Storage Disease Program, Biochemical Genetics Training Program, and Metabolic Clinic at Duke University Medical Center.
Dr. Kishnani has worked in translational research throughout her career. She has worked to apply basic scientific discoveries to clinical trials and has pioneered the approval of new therapeutics. Dr. Kishnani’s work has crossed over into the field of newborn screening at many points in her research career but specifically through her work in the care and treatment of individuals with lysosomal storage disorders (LSDs), glycogen storage diseases (GSDs), and other inborn errors of metabolism. She has served as a principle investigator on several clinical trials with a primary focus on the clinical implementation and development of new therapeutic interventions, specifically with a focus on enzyme replacement therapy and small molecules. She remains passionate about the care, treatment and natural history of individuals with LSDs.
Dr. Kishnani has been widely published in journals, textbooks and scientific reviews in the areas of treatment strategies, and examining long-term complications in various LSDs. She dedicated over 16 years of her career to developing a treatment for Pompe and has been recognized as an advocate for awareness of Pompe disease as well as many other rare diseases.
Erin Huggins, MS, CGC
Erin Huggins is a board-certified genetic counselor at Duke University in the Division of Medical Genetics, Department of Pediatrics. She received her B.S. in Biology from Coastal Carolina University in 2016 and her M.S. in Genetic Counseling from the University of South Carolina in 2018. She provides clinical genetic counseling for patients across the lifespan with a variety of inherited diseases including glycogen storage diseases, lysosomal storage diseases, and other inborn errors of metabolism. In addition to her clinical role, Erin is a member of Dr. Priya Kishnani’s research team and is involved in a number of research activities related to metabolic disease. Her primary areas of interest are newborn screening for Pompe disease and clinical variant interpretation in rare diseases. Erin is originally from Charleston, SC, and currently resides in Durham, NC.