Rare disease day 2023: Surprises & challenges in rare disease research

On Rare Disease Day 2023, Prof. Carole Linster from the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg reflects on her team’s work on metabolite repair disorders, a subset of the over 7,000 rare diseases identified to date. Most of these diseases have a genetic background, and an estimated 300 million people globally are affected, including 30,000 in Luxembourg alone.

Prof. Linster’s group focuses on (neuro)metabolic conditions caused by the accumulation of harmful waste products due to malfunctioning cleanup mechanisms. Prof. Linster shares how her team got into rare disease research, a recent surprising discovery and why collaboration is essential to tackle the many challenges in this field of research.

How did you and your team get into rare disease research?

At heart, we are a biochemistry team working on discovering novel enzyme activities. Even though we know the complete human genome sequence since 2001, there are still thousands of genes with unknown functions, including many enzyme-encoding genes. Together with multiple international collaborators, we could link some of the novel enzymes we discovered to human diseases. Building on these advances, we look for potential treatment strategies for both newly discovered and previously known rare diseases, by developing disease models and by using the state-of-the-art large-scale screening capabilities of the LCSB.

Can you give us an example?

In 2011 we discovered a new enzyme called NAXD involved in cleaning up a metabolic side product, which becomes toxic to cells when it accumulates. In 2017, we were contacted by clinicians who had identified children in five different countries (from four different continents) with severe neurodegeneration and skin lesions. All patients had a mutation within the gene coding for NAXD, and we were able to show that this genetic defect was indeed responsible for the illness. Based on our previous research, we could propose potential first treatment options: vitamin B3 proved to overcome some aspects of the defective metabolism. In addition, we discovered that the mutated enzyme became unstable with heat, which could, in turn, explain why the disease manifested in these children after an otherwise unremarkable fever.

So, NAXD deficiency is a fever-triggered rare disease that only affects children?

This is what we thought until recently. But surprisingly, we were contacted for a new case where the disorder manifested in an adult patient after mild head trauma. It turned out that the patient in his thirties also carried a mutation in the gene encoding NAXD but didn-t know about it. He had a history of recurring oral ulcerations managed with vitamin B3, B12 and folate, but he had stopped taking the supplements about six months before the accident. Instead of a fever, it seemed that a mild head trauma had triggered the onset of neurodegeneration in this adult patient. When the underlying genetic cause was identified, administering a high dose of vitamin B3 did indeed stop the progression of the disease. Still, the damage caused by that point was already too severe, and the patient was moved into palliative care. In the next step, we are now trying to understand the commonalities between these cases to understand how the disease is triggered and hopefully prevent its onset.

What are the challenges in rare disease research and care?

The example of the NAXD patient shows how important it is to get the correct diagnosis quickly to be able to give the proper treatment if one is available. Unfortunately, the diagnostic process for rare diseases is often extremely long, with around five years on average. This can be attributed to the fact that less than 1 in 2000 people (often even far less) are affected by a given rare disease, so most doctors might have never come across patients with the corresponding symptoms before. As a single rare disease can manifest quite differently between patients, it can even get more complex. When trying to uncover the genetic cause of a rare disease, we need at least two, ideally more, patients with similar symptoms and mutations in the same gene to firmly establish the link between genotype and phenotype.

Furthermore, treatments are estimated to only exist for 6% of rare diseases at the moment, not the least because funding for rare disease drug development is scarce considering the low number of patients with a given disease. Once the genetic cause of a disease is identified, researchers can create disease models like cellular or animal models that recapitulate aspects of the disease to study their mechanisms and to look for new treatment strategies. Screening libraries of drugs already approved for treating other diseases can lower costs and accelerate the development of rare disease treatments.

Both the diagnosis of rare disease patients as well as research on underlying disease mechanisms and drug development require broad international and interdisciplinary collaboration: clinicians, bioinformaticians, and laboratory researchers must work hand in hand to put the different pieces of the puzzle together. Only as a team can we understand the mechanisms of diseases and try to improve the quality of life of patients and their families.

The paper describing the surprising adult case of severe neurodegeneration after head trauma was recently published in the International Journal of Molecular Sciences.

Learn more about Prof. Carole Linster’s work, which led to an FNR award for Outstanding Scientific Publication in 2020 .

Prof. Linster’s research on NAXD is funded by the Luxembourg National Research Fund (FNR), the Juniclair foundation and the Lions Club Luxembourg. Other research projects on rare diseases are funded by the LCSB Internal Flagship Grant, donations from ATOZ foundation, LOSCH foundation, Rotary Club Luxembourg, Lions Club Luxembourg, & private sponsors. www.rarediseaseday.org