Seven out of every 100 people worldwide are affected by one of about seven thousand rare diseases known. On Wednesday, February 29 marks the World Day of rare diseases and we wanted to know the work that some of the IDIBELL groups who are investigating these syndromes.
In the area of epigenetics, led by Manel Esteller, the researcher Maria Berdasco studies Sotos and Rubinstein-Taybi syndromes, Dori Huertas investigates Rett syndrome and Ethel Queralt group investigates the Cornelia Lange syndrome.
"The majority of rare diseases that we study here," explains Maria Berdasco "are result from genetic mutations in genes that have epigenetic activity (in charge of placing chemical markers in the DNA that affect the expression of several genes) causing consequences on the individual ".
Currently, these diseases are not yet well characterized; it is known several genetic alterations with physical consequences such as motor dysfunction, physical abnormalities and mental retardation in varying degrees, are repeated in all. "What we study at the lab are the consequences of this alteration and we assess whether they can be evaluated as potential therapeutic targets," said researcher Maria Berdasco.
Sotos syndrome is a genetic disease included in the so-called overgrowth pathologies. It is characterized by an oversized body and head, a characteristic physiognomy and learning difficulties. It is present on one of 10,000 to 50,000 children just born but they do not show symptoms until 15 months or four years.
Several therapies are used to treat some symptoms such as speech learning or other therapies to treat the hyperactivity associated with some patients, but there is no drug therapy to treat the disease.
In 60% of patients it has been identified mutations in the NSD1 gene that has an epigenetic function. If this gene is not expressed, alters the epigenetic marks of certain sequences of the genome, which generates consequences for the individual.
"The main goals of our group," says Berdasco, "is to know the molecular basis of disease, look for markers that facilitate the diagnosis and guide the search to therapy." According to the researcher "molecular knowledge of the disease opens the door to new therapeutic avenues, such as testing drugs that restore the altered epigenetic patterns in patients or in the case of alterations of a single gene, using gene therapy to restore the error."
However, in this sense, Berdasco thinks we're very far because "for example in the case of Sotos syndrome only 60% present the NSD1 gene altered, there is still 40% who we do not know why they have the disease."
The group has also published that alterations in this gene which cause Sotos syndrome are involved in the development of tumors in the nervous system. This work has set the current foundation for research group in Sotos syndrome which is currently focused on the possible involvement of other epigenetic control mechanisms as non-coding RNAs in the genesis of the disease.
Rett Syndrome is a genetic disease that affects neurological development. It occurs in one in 15,000 children born at Western world. It is a very serious disease that involves mental retardation, cognitive and motor to varying degrees.
80% of girls who have this disease have mutated MECP2 gene. This gene is located on chromosome X (and occurs only in girls because children with this mutated gene do not survive), and controls epigenetic mechanisms in multiple pathways in the brain.
"This gene," explains the researcher Dori Huertas, "is called orchestra director because it regulates many important metabolic pathways and its mutation affects many other genes in these pathways." Mutations in two genes, CDKL5 and FOXG1 also cause Rett syndrome with more severe forms but it is unknown what the exact relationship of these two genes with MEPC2 ". And there are a 10% of girls with Rett's symptoms that do not exhibit any of these three mutations. This is called non- filiated Rett".
Currently, they are developing three lines of research. "On one hand, we are working with mouse models, to which they removed the gene MEPC2" used to compare differences in gene expression between these mice with Rett syndrome and normal mice. "From these data we have dared to try different drugs with this mice model, some already used in other neuronal diseases and new ones. Now we are analyzing the results and we will have definitive data soon”.
On the other hand "we continue to seek new therapeutic targets by using new technologies such as ultrasequenciation of brain samples from mice, "we will be able to find more subtle variations in gene expression. With this technique we refine more from the therapeutic point of view. "
And finally, they also use ultrasequencing to identify mutations of girls who have an orphan mutation Rett syndrome. "We are able to sequence the entire genome to increase the probability of finding the mutated gene. It is important to know which the altered gene is because it could be used in therapy in these girls; And of course, its relevance to understanding the molecular mechanisms of disease.”
Cornelia Lange Syndrome
The Cornelia de Lange syndrome is a non-hereditary genetic disorder that causes severe abnormalities in embryonic development. Its prevalence was one in 10,000 children born, but it has declined in recent years because it can be detected prenatally. According to researcher Ethel Queralt this fact makes "that only less severe cases are born but they are also the most difficult to diagnose".
This syndrome is characterized by a delay in the development of growth, newborns have a size smaller than average, and they could lack of some fingers or a hand. They have gastric problems; a few years ago it was a death cause, vision problems and lack of physical development of puberty characteristics.
The disease is diagnosed by facial features like eyebrows together in the middle, or lips inverted V-shape ... which may be common to other syndromes and also can occur in very different degrees among patients.
Eight years ago it was discovered that 60% of patients have a mutation in the NIPBL gene, related to cohesin (proteins involved in cell division, mitosis). And two years later it was found that mutations in two other SMC1A nothing and SMC3 also cause the disease. "Initially," explains Queralt "did not appear that the two processes were related but now we are studying another possible function of cohesin that is altered in children with this syndrome."
Between 20% and 30% of cases of Cornelia de Lange syndrome have no mutation assigned.
Diagnosis and Financing
The three researchers agree that the biggest problem is the difficulty of diagnosis, because, first, they are diseases of low prevalence and physicians may find it difficult to diagnose, secondly there are a variety of symptoms that are common to different diseases and clinic cannot always assume the cost of genetic diagnosis that, warns Mary Berdasco, "does not always work because they are not identified all the genes that cause disease. For example in Sotos syndrome only 60% of patients have NSD1 gene mutation".
The other obstacle is the difficulty to secure funding for research into these diseases that affect relatively few people compared to cancer or cardiovascular disease, for example. In any case, all three agree that whenever there is a greater awareness of the need to study these diseases. "Parents of children affected," says Ethel Queralt "are aware that what is being investigated now probably will not result in short-term in a treatment for their children but just knowing that somebody is working on it makes them feel accompanied ". In some cases, such as that of the Catalan Association of Rett syndrome, explained Dori Huertas, "they are who had helped us to finance projects." But all three understand that research on rare diseases cannot rely solely on the contributions of the families.
Other rare diseases
These three syndromes are just one example of the research conducted in IDIBELL in the field of rare diseases. Researchers at the institute investigate, among others cystic fibrosis, thrombophilia and gastric cancer, cystinuria, Wolfram syndrome, family poliposi, neurofibromatosis, hereditary breast and ovarian cancer syndrome, X-linked adrenoleukodystrophy, Ewing sarcoma or leukoencephalopathy with megalencephalic subcortical cysts .