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“It is about terrible fates” – An interview with Eva Luise Köhler and Prof. Dr. Corinna Grasemann

Rare diseases are not as rare as the term suggests. Four million Germans suffer from them, many of them children. In an interview with the Frankfurter Allgemeine Sonntagszeitung, Eva Luise Köhler and the pediatric endocrinologist and head of the Center for Rare Diseases at the University Children's Hospital in Bochum, Prof. Dr. Corinna Grasemann, talk about how to better help the "orphans of medicine", what possibilities genetic diagnostics offers today and why people also have a right not to know.

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Mrs. Köhler, it is one of the unwritten rules that the wife of the Federal President takes on patronage. After your husband’s surprising resignation at the end of 2010, you have remained true to one topic: rare diseases. How did you come to take on this patronage?

Eva Luise Köhler: The wife of the Federal President does indeed receive a lot of inquiries. One of them came from the then quite young association Allianz Chronischer Seltener Erkrankungen, ACHSE for short. It was immediately clear to me: you have to do this. I was already familiar with the problem from former First Lady Christiane Herzog’s impressive advocacy for cystic fibrosis. I thought to myself: now is the time to bring the overall problem, which applies to all rare diseases, into the public eye.

What impressed you so much about Christiane Herzog’s commitment?

Eva Luise Köhler: Without Marianne Herzog, cystic fibrosis would not have become a well-known disease. Thanks to the research that her foundation has driven forward, therapeutic progress has been made. As a result, children with the disease no longer regularly die at a young age. They have the chance to grow up. This is a typical example of how research gives hope. But it still usually takes many years for rare diseases to be correctly diagnosed. In many encounters with patients, I have experienced many times how exhausting the path to a diagnosis can be. I well remember a little boy who first started to walk and talk normally and developed well – but then suddenly fell frequently, developed behavioral problems, could no longer see well, had epileptic seizures and couldn’t keep up with his studies. A new specialist was consulted for each abnormality until the boy was finally admitted to one of the Centers for Rare Diseases at a university hospital, which now exist thanks to the National Action Plan of 2013. There it was discovered that he was suffering from lysosomal storage disease (LSD). In LSD, a lack of enzymes leads to disorders in the breakdown of metabolic products.

The odyssey was over for the parents and the boy . . .

Eva Luise Köhler: On the one hand, this was a relief. However, it was shocking for the parents to learn that there is no treatment for this disease. Something I really admire: Despite all their worries, many sufferers, like this family, get involved after a diagnosis, for example by setting up self-help groups or making their case and knowledge available to research – even if they know it probably won’t help their child.

The term “rare disease” is misleading as to its true extent

When you took over the patronage, five patient self-help groups had just been organized in the ACHSE . . .

Eva Luise Köhler: . . . and today there are already more than 120. This highlights an aspect that is important to me: the term “rare disease” is misleading about the true extent. Each individual disease may be rare or even ultra-rare, but in Germany alone at least four million people are affected by rare diseases – more than by some common diseases.

Interesting change of perspective.

Eva Luise Köhler: It is precisely this change of perspective that we are concerned with on several levels. At first glance, it hardly seems worthwhile to develop new therapies due to the low number of cases. However, rare diseases have long since proven to be a beacon for the future of medicine – personalized precision medicine.

Professor Grasemann, you head the Department of Rare Diseases at Bochum University Hospital for Pediatrics and Adolescent Medicine. Can you give us an overview of rare diseases?

Corinna Grasemann: Oh, that’s a challenge! After all, there are more than 6000 very different rare diseases, from bone diseases to metabolic diseases, tumor diseases and neuromuscular diseases. And more than 200 are added every year as a result of diagnostic progress. As a general rule, a disease is considered rare if it affects fewer than five in 10,000 people. The vast majority of rare diseases are practically unexplored, and often only the symptoms can be treated – typically with drugs that are not or not yet approved for the disease. There are currently only special drugs for around 130 rare diseases. They are called orphan drugs because they are intended for the proverbial orphans of medicine. The vast majority of rare diseases are genetic and occur in childhood. Many people are probably not aware of this: Almost all children who still die from medical problems in Germany today die from a rare disease. That’s more than 1000 children. Year after year.

The enormous increase in knowledge in medicine is an opportunity of the century

Eva Luise Köhler: We are talking about really bad fates. I remember the parents of a child with spinal muscular atrophy type I. This hereditary disease, known as SMA for short, causes nerve cells in the spinal cord and brain stem to atrophy. Muscle weakness and atrophy progress inexorably. Until now, the disease has been considered incurable, with children dying at the age of two or three – and yet it is an example of how great the potential of research is. In 2021, an affected girl at Heidelberg University Hospital received gene therapy at the age of 23 days thanks to newborn screening. Powerful diagnostics and high-precision therapeutic procedures open up completely new possibilities for intervention. This is an opportunity of the century. We are currently experiencing an enormous increase in knowledge in medical research.

Professor Grasemann, which one is that?

Corinna Grasemann: It really is a huge improvement and acceleration in genetic diagnostics. We can now understand and treat the causes of diseases better than ever before. When I started my medical career, you had to think carefully about which gene you wanted to examine in search of a disease. It often took months to get a result. Today, thanks to advances in genetic diagnostics, broad screening is possible and many diseases can be detected before symptoms even appear. Early diagnosis is so important because help is often much better at this stage and progression of the disease can be slowed or even prevented. Even with diseases for which there is still no cure, children can often achieve a good quality of life, and for families a diagnosis often means the end of agonizing uncertainty, even if no cure is possible. For some diseases, such as cystic fibrosis or congenital forms of obesity, there are now effective drugs that have been specifically developed thanks to research into their genetic causes.

Genetic diagnostics generates enormous amounts of data – is that not a major challenge?

Corinna Grasemann: The amount of data is not the only challenge. A person has thousands of different genes, and each of us carries some kind of change in our genetic material. This is completely normal and has no health consequences for the vast majority of people. So when you genetically examine a patient, you have to filter very carefully to find out which changes are relevant for a possible rare disease.

So it is also about not worrying people unnecessarily?

Corinna Grasemann: That’s right. The enormous progress also presents us with ethical problems. One example: A child with short stature is treated in the consultation. The diagnosis shows that it is genetically caused short stature. But we also find a genetic change that we know is associated with a severe developmental disorder. However, the child does not yet have a developmental disorder, but attends a secondary school. You can imagine how challenging it is to explain such so-called random findings to parents without causing anxiety. Knowledge about the genetic causes of rare diseases is growing at breathtaking speed – as is the challenge of dealing with this knowledge responsibly.

Eva Luise Köhler: Especially as there is a right not to know.Nobody needs to know what diseases they may have.Most people wouldn’t be able to cope with it mentally, and I probably wouldn’t either. But that’s not the point.Newborn screening is about diseases that, if left untreated, can lead to severe disabilities or death in the first few years of life.For an increasing number of them, there are now treatment options that can avert great harm if they begin before the onset of symptoms. Take the disease SMA, which we have just mentioned. If I knew that there was a chance that my child, who was only a few days old but doomed to die, could be cured by gene therapy, then as a mother I wouldn’t give it five minutes thought!

Doctors should remain open minded for the unexpected

Why is it that it often takes many years before a rare disease is diagnosed? Are doctors in private practice not adequately aware of rare diseases, or are they perhaps blocked by established medical routines from dealing with the usually highly complex clinical pictures?

Eva Luise Köhler: In medicine, there is the saying “When you hear hooves clattering, think of horses and not zebras.” This is intended to make it clear that common diseases are more likely than rare ones, even if a patient’s symptoms would fit both. This is true in most cases. But this makes it all the more important to remain open-minded to the unexpected. For example, if a dentist is faced with a small child whose teeth are falling out, they certainly don’t have to immediately recognize that it could be a form of hypophosphatasia. But he should be suspicious, admit to himself if he doesn’t know what to do and seek advice. That’s my plea to all doctors.

Corinna Grasemann: Thanks to the tireless lobbying work of ACHSE and the Eva Luise and Horst Köhler Foundation, there is now a network structure for this in Germany. Today, there are overarching centers for rare diseases at 36 university hospitals, and numerous other specialist centers are being added – all of which can be easily researched on the Internet. Partners of the Köhler Foundation are currently setting up a national registry for rare diseases so that valuable information for research and care is not continuously lost as it has been in the past. And unlike during my studies – I can’t remember ever having heard the term “rare disease” – there are now seminars and lectures on the subject at universities. Because the diseases are so different, you can’t offer budding doctors a general rule like “if you see this or that symptom, it’s a rare disease”. But you can teach them that the alarm lights should be recognized whenever symptoms occur very early in life, for example.

Does this also apply to common diseases such as obesity?

Corinna Grasemann: Obesity is a good example. This disease affects 40 to 50 percent of adults and more and more children. In the vast majority of cases, obesity is caused by our changed lifestyle. It therefore makes sense to regard a fat child as one of many fat children. But if you have a two-year-old boy in front of you who is very overweight, then as a doctor you should recognize this: This is probably the zebra among the horses, this is probably monogenetic obesity, even if it only affects a few hundred people worldwide.

Is there any help for such obese children?

Corinna Grasemann: Yes, but it took more than 20 years. Patients with an alteration in the pro-opiomelanocortin gene, or POMC for short, suffer from a deficiency of the hormone of the same name, which is why they are simply constantly hungry. The disease leads to severe obesity as early as the first year of life, from which patients used to die at some point. Today, there is a drug that can correct the faulty signaling pathway. As a result, people reach their normal weight and can lead a completely normal life.

Research is the key to better health

Because research into rare diseases is not the focus of university medicine in Germany – only the Charité names it as one of its priorities – your foundation has launched a research initiative. Together with partners from university medicine and civil society, you are collecting donations to ensure that more young doctors can conduct research into rare diseases. And since 2008, there has been the Eva Luise Köhler Research Award, endowed with 50,000 euros, which is being presented this week. Who is being honored in your name this year?

Eva Luise Köhler: With Alessandro Prigione and Markus Schülke, we are honoring two scientists in 2024 who are working intensively on mitochondriopathies. This means that the so-called “cellular power plants” do not work properly, which has a huge impact on overall development. Through systematic studies, our prizewinners have discovered that the active ingredient sildenafil, which was previously known primarily as “Viagra”, also has very positive effects on mitochondria. The findings could also be applicable to other rare and previously incurable diseases. What is important to me in this context is that the award should draw attention to the urgent need for research into rare diseases, create public awareness of this important topic and drive forward the development of the research field. That’s what it’s about, not the name.

Corinna Grasemann: Research is indeed particularly important in order to improve care and also to achieve small “miracles” such as the treatment of the rare congenital form of obesity. This is another reason why the centers are affiliated with university medicine.

What’s next for rare diseases?

Eva Luise Köhler: There is still so much to do! The National Registry for Rare Diseases urgently needs to be developed further. Something like this has long existed in France. But we are falling short of our potential because we are still not bringing together all the available information digitally. It is also unacceptable that funding for the centers for rare diseases has not yet been secured in all federal states. We need to work through the National Action Plan for Rare Diseases from 2013, drive research forward and create structures so that the new methods and findings also reach patients.


The interview was published in the Frankfurter Allgemeine Sonntagzeitung on April 28, 2024. The questions were asked by Reiner Burger.

Pictures: Olaf Schwickerath/ Andrea Katheder


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