How are rare diseases defined?

Rare diseases are defined by a public health approximation of frequency or prevalence. A disease is considered rare when it does not affect more than 1 in 2,000 live births. So, we have created a rather arbitrary frontier between common disorders – such as hypertension, Alzheimer’s, cancer or psychiatric diseases – and rare disorders.

There are also more subtle definitions and components of rare diseases. Most rare diseases are genetic in origin, but not all; there are rare infectious diseases, for instance. Still, 80% of rare diseases have a genetic background, whatever the model. This genetic origin may be the alteration of a segment of the genome, the mutation of a gene, a complex mechanism or a complex combination of genetic predisposition.

Photo by Mirkola Chupirta

Since most rare diseases have a genetic origin, some rare diseases are also hereditary. Rare genetic diseases often involve family history and affect family plans for the future. As a result, such diseases can be a heavy burden on parents, as well as children, throughout their lifetime.

Rare diseases are also extremely diverse. They can range from bone dysplasia to neurological dysfunction, kidney anomalies or haematological phenotypes, to give a few examples. At the same time, rare diseases share some natural history features. First, most of them are severe. Second, most of them are lifelong disorders. A person born with a rare disease will also die with it, regardless of whether they die of it.

Diagnostics and treatment

Diagnostics is still an issue for rare diseases. For about only half of these diseases, genetic testing can reveal a diagnosis and name the patient’s enemy. And finally, only 10% of rare diseases have a specific treatment. Of course, medicine, surgery and other treatment options are available to help patients. But by specific treatment, I mean a treatment that is based on the mechanism of the disease. This could be a treatment derived from genetics, gene therapy, though not necessarily. Nonetheless, only 10% benefit from a specific treatment. This shows how difficult the landscape of rare diseases is.

Individually, some of these disorders are exceptional, or even unique to a country. There may be only one or two families affected. But, collectively, 1 in 2,000 live births means that rare diseases affect millions of people: 3 million people in France, 30 million people in Europe. The viewpoint of rare disorders is thus extremely different from the families of affected patients and from everyone else. Rare diseases are rare. Most people don’t care. But from the individual viewpoint, wherever you are in the world, there is not a single family that is not affected by one individual with a rare disorder.

One of the biggest challenges for addressing a rare disease is to recapitulate its natural history. When does it start? What are its main symptoms or features? When is it time for a diagnosis? Finally, at what point does a physician, a counsellor, a paediatrician or other doctor send the patient to a place with the right expertise?

Building a pathway for patients

In Europe, North America, Japan and other developed countries, the expertise for rare disease is outstanding. But the question is how to reach that point. One of the ideas that has been promoted by France, as well as many countries in Europe, is a rare diseases plan. The public health system has to propose a general matrix to help families to find their way in the health system.

For common disorders, the system is usually well organised, or at least navigable. A general practitioner refers a patient to a university hospital, as needed, and the patient then goes back to the GP. People have found that to be practical. But for the rare disease patient and family, this track from the general practitioner or general paediatrician to the expertise might take years. This is extremely challenging for families because, in addition to the symptoms, there is the sense of being under a curse as the child has a condition which nobody seems to know anything about.

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The national rare diseases plan in France, which is now in its third edition, has tried to generalise expertise by building reference centres for rare diseases. There are just over a hundred centres in France. And these centres are really reference networks, places with the combined expertise of clinics, clinical research, molecular diagnostics, treatment options and patient follow-up. The Imagine Institute, which I direct, is based on these ideas of combining clinical expertise with research to accelerate knowledge in rare diseases. Ultimately, the mission of such centres is to spread this knowledge across a wider network so that wherever patients are born, they can find a pathway from diagnosis to care and treatment.

Corentin’s journey

The story of Corentin and his family shows the difficult journey of the family of a child with a rare disease. Corentin is a charming boy born five or six years ago to a healthy family in Paris. The first year and a half of his life are fine. Then he starts to walk a bit late. When he walks, he falls with what we call ataxia, which means imbalance. In addition, Corentin has delayed speech organisation, which doesn’t match his understanding. You see that Corentin understands much more than he can say; he would love to express himself by oral communication and cannot do so. Finally, Corentin has what we in the paediatric and genetic medium call dysmorphic features, or peculiar facial features. There are neurological symptoms and some clues in the clinical examination that this particular case could be due to a rare disorder not yet diagnosed.

Photo by AnnGaysorn

Corentin begins his journey from one paediatrician to another, from one hospital to another. The colleagues are excellent; the question is not there but in obtaining more data through an MRI, through a muscle biopsy. The story of Corentin turns into a medical story, and this is extremely difficult for the parents. They turn to genetics and the Imagine Institute, where I begin to see Corentin at the age of three.

A genetic odyssey

We start with the classical work of a geneticist, looking at the MRI, looking at the structural variations in the genome by karyotype, by a comparative genome, hybridisation, high-performance techniques and then going to candidate gene hypotheses. We spend months, if not years, looking at one gene and another, saying: we don’t know. Those are terrible words for a physician to say. But they are also the words that the parents would like you to say when necessary because it’s better to say, ‘I don’t know’ and explain what you will do next than to not say anything.

We started with high-throughput techniques of next-generation sequencing with Corentin, and we found not only one mutation in the gene but at least three genomic variations that could each be responsible. So, the diagnostic odyssey did not stop with next-generation sequencing but started again because there were not one but three guilty variations.

After another look at Corentin’s genome with international collaboration, we could say: we’re not sure, but we think this variation of chromosome 14 in that gene is the cause of Corentin’s disorder. Through genetics, we can see that this variation is not inherited from either of the parents. It could be a mutation in Corentin’s genome.

The relief of knowing

For the parents, this was a relief because it was the first time that they had a name. The name of a gene is nothing, because there is no immediate treatment. But the parents told us that, at last, they knew that there was something in Corentin’s genome causing his disorder. It was not their fault; the pregnancy was ok; it had nothing to do with their lifestyle. It was written in the genome. The second relief was discovering that the condition is genetic, but not hereditary. There was little or no risk for a second child, which the parents are having now.

The next question was to understand why this variation in that gene produces the phenotypes or features of Corentin. Corentin’s case was so rare that we had no other case in France, to the best of our knowledge. We built an international collaboration with colleagues in Italy and the UK. They mentioned the variation in the same gene. We asked: what are the features of your patients? And we shared data between those three centres, coming to the conclusion that, yes, indeed, these genes might well be the gene. The features of those three children in Europe are very similar. Once again, for the parents, this cooperation between countries was crucial to add a little more to the little knowledge we have.

A new odyssey of treatment

After identifying the gene, the question becomes: can we do something? Can we change it? Unfortunately, we could not repair or change the genome. So, a new odyssey started. How could we modify Corentin’s phenotype by using any means possible to change, if not the gene, then the expression of a gene – by using a protein, or by repositioning an abandoned treatment for something else, for example?

The story of Corentin gives a bitter taste of the years of odyssey between having a child with symptoms you do not understand to arriving halfway, discovering that it is genetic. We know that it is not hereditary. We know that we have a guilty gene in this story. And we know that many things can start from that point. But now we have a second odyssey ahead towards modifying Corentin’s disease.

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Hubert, L., Cannata Serio, M., Villoing-Gaudé, L., et al. (2020). De novo SCAMP5 mutation causes a neurodevelopmental disorder with autistic features and seizures. Journal of Medical Genetics, 57(2), 138–144.

Chen, X., Garcelon, N., Neuraz, A., et al. (2019). Phenotypic similarity for rare disease: Ciliopathy diagnoses and subtyping. Journal of Biomedical Informatics, 100.

Boisgontier, J., Tacchella, J.M., Lemaître, H., et al. (2019). Anatomical and functional abnormalities on MRI in kabuki syndrome. NeuroImage: Clinical, 21.

A child with a rare genetic disease: the story of Corentin