Rare diseases - not so rare all together!

This image for Image Layouts addon
Raphael Gindt

Rare diseases are those that affect less than 1 in 2,000 people. While an individual disease might be labeled as "rare", the total number of persons in Europe suffering from one of the over 7000 different identified rare diseases is estimated at over 30 million. According to ALAN – Maladies Rares Luxembourg, there are approximately 30.000 individuals concerned by rare diseases in Luxembourg. Nearly 80% of rare diseases are of genetic origin and many of them affect the brain. They are present throughout a person's entire life, even if symptoms do not appear immediately.

At the LCSB we study several rare diseases that are caused by genetic mutations leading to chronic and life-threatening symptoms. For the development of novel therapies, it is essential to identify the underlying genetic cause and to understand the molecular mechanisms underlying the disease.

NAXD deficiency: devastating effects triggered by fever

Recently, Dr. Carole Linster and collaborators have identified the genetic cause of a severe novel childhood disease called NAXD deficiency. Affected children suffer from episodes of neurological regression triggered by mild fever or infection, neurodegeneration, and skin lesions, eventually leading to early childhood death. The researchers have discovered that NAXD is a metabolic repair enzyme. Such enzymes make sure that unwanted or toxic metabolic byproducts get converted into molecules that are not harmful for the cells. In the patients, the enzyme does not function well. Hence, toxic molecules accumulate and damage the cells. In a next step, the team is currently recreating this same genetic defect in zebrafish and in nerve cell cultures generated from patients’ stem cells. We aim to mimic the disease in these models in the lab to better understand how the disease develops and to start testing therapeutic approaches.

Zebrafish and yeast to study rare diseases

The team also studies other rare diseases in yeast and zebrafish models to screen for small molecules with potential disease-modifying properties. Did you know that even the traditional baker’s yeast, which is for instance used for making bread or brewing beer, has up to 30% of the genes that are known to cause diseases in humans? In the lab, we can introduce patient mutations into the corresponding yeast genes to mimic and study the corresponding diseases.

Drug Screen Model Systems
This is the case for Juvenile Batten disease for example, the most common inherited neurodegenerative disease in children. Mutations in the gene ATP13A2, which is also implicated in a juvenile form of Parkinson’s Disease, trigger seizures, changes in personality and behavior, speech and motor skill problems in children. Efficient treatment options for this fatal disease are currently not available. Testing hundreds of molecules in the ‘Batten disease’ yeast and zebrafish models, the LCSB researchers have now found two drugs, one of which is already used in humans for other diseases, and that reversed the effect of the Batten disease mutations in the yeast and fish models. In a next step, the efficiency of these drugs needs to be investigated in mice before they can be tested in Batten disease patients.

Recently, the team also started a project on Zellweger syndrome, a peroxisome biogenesis disorder. As a result of impaired peroxisome function, Zellweger patients accumulate very long chain fatty acids and branched chain fatty acids that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems, leading for instance to impaired brain development, seizures, decreased muscle tone and liver dysfunction.

Drug development for rare diseases is often not supported by pharma industries because of the low number of patients affected by the individual diseases. We are grateful for the financial support we received from various funding sources including the Luxembourg National Research Fund (FNR), the University of Luxembourg, the ATOZ foundation, the LOSCH foundation, the Juniclair foundation, the Lions Club, the Rotary Club, the Association Luxembourgeoise des Amis de la Fondation Louvain, and private donors.

For further information, please visit: