We are incredibly excited to announce that we are partnering with Dr. Eva Morava at Mt. Sinai Medical Center to create a research study focused on Nora!!
Dr. Morava and her team will be growing brain organoids based off of Nora’s cell line. A brain organoid is like a tiny, 3D model of parts of a human brain, and is grown in a lab from stem cells. Think of it as a “mini-brain,” but without the complex connections and functions of a real brain.
So, what is the purpose of these mini-brains? Let me begin with a little recap on what we know to date about Nora’s gene variants.
Nora has variants of uncertain significance on two genes linked to neurological disorders, PAX5 and ALG13:
PAX5 - The landscape around genetic research on PAX5 is very nascent, with the gene recently being linked to neurodevelopmental disorders in 2021. Nora was part of the first cohort featured in a research publication linked here. Nora’s seizures and developmental delays are by far the most “severe” of the cohort. We recently received some news that other healthy individuals have been identified with her variant, making it less likely to be the cause of her disorder than we initially thought.
ALG13 - Variants in this gene are associated with an ultra rare disorder called congenital disorder of glycosylation (CDG). ALG13 CDG affects less than 100 people, and the vast majority are girls with a common ‘de novo’ (uninherited) variant. Nora’s variant is in a different location, it is inherited, and she has many unaffected family members with the exact same variant.
With respect to ALG13 CDG, although the inheritance pattern doesn’t add up, for a long time we have been suspicious of how well Nora matches the phenotype of the disorder. To make it more complex, until recently there was no biomarker for ALG13 CDG. A biomarker is something you can test in blood, skin, or other tissue that would confirm the presence of a disease or disorder.
Now, Dr. Morava and her team have a way to definitively test for ALG13 CDG. Unfortunately, it can only be tested for in brain tissue. Here is where the mini-brains come in! Our whole family will be heading out to Mt. Sinai in December to donate fibroblasts (skin cells) that they will turn into stem cells and begin the creation of our own mini brains. The research team will use these brain organoids to test for glycosylation abnormalities.
What will the results tell us?
If Nora’s mini brain shows abnormal glycosylation, then it will indicate that she does, in fact, have a congenital disorder of glycosylation. Assuming the brain organoids of her unaffected family members who have the same variant are normal, we would conclude that there is likely a second factor only present in Nora’s genetics that is working in conjunction with her ALG13 variant to cause the disease expression.
If it shows normal glycosylation, that would be strong evidence that the ALG13 variant truly is a red herring.
While it’s frustrating that Nora is the ultra-rare outlier or the exception to the rule time and time again, it’s often the corner cases that reveal the most about the mechanism of a disease or disorder. We are incredibly excited to see what this research reveals.
I can’t believe it’s been almost two years since we launched the foundation, and over 4 years of personally searching for answers. Thank each and every one of you who have donated to the Finding Nori Foundation for making this research possible. If you have given a single dollar, participated in any of our fundraisers, or simply shared Nora’s story - I hope you know how valued you are and how important you have been in getting to this moment.
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