At FMUL, health debates are just a click away. This time, and on the occasion of the celebration of World Rare Disease Day on 29 February, we again gathered a panel of excellence in the Dr Paul Janssen Room for another edition of e-Talks, which took place on 27 February.
The debate was coordinated by Doctor Luís Brito Avô, Head of the 1D Medicine Sector at the Northern Lisbon University Hospital Centre (CHULN) and also Founder and Coordinator of the Rare Disease Studies Centre (NEDR) of the Portuguese Society of Internal Medicine (SPMI) .
As usual, guests and professional colleagues gathered to discuss the outlook of rare diseases in Portugal.
From the current perspectives to the vision for the future, there were many topics under discussion, namely, the conditions of diagnosis, forms of treatment and new therapeutic possibilities, the importance of national reference centres for the provision of health care to patients with rare diseases, the prominent role played by patient associations which, working closely with doctors and health professionals, help to envisage a very promising future with regard to research and direct intervention with patients.
At the table sat Doctor Anabela Oliveira, responsible for the Reference Centre for Hereditary Metabolism Diseases (CR-DHM) of the Northern Lisbon University Hospital Centre (CHULC); Dr Isabel Conceição, Neurologist at the Lisbon Medical Academic Centre and Coordinator of the Reference Centre for Familial Paramyloidosis; Dr Patrícia Nunes, Director of the CHULC Dietetics and Nutrition Service; Professor Simão Rocha, Biologist and Researcher at the Institute of Molecular Medicine and also Dr Patrício Aguiar, Internal Medicine Physician at Santa Maria Hospital and professor at FMUL.
The remaining guests participated from other parts of the country and the world by means of a new webinar system.
The starting point for the debate was the reflection on the “purely statistical” concept of rare disease, since 30 years ago it was not part of the clinical lexicon, in addition to the fact that a doctor can spend a lifetime without diagnosing a case because they are extremely unusual.
It is a rare disease that has an incidence of one case per 2,000 people. There are around 300 million people in the world with a rare disease, of whom 36 million are European. It is estimated that, in Portugal, there are between 600 to 700 thousand Portuguese with a diagnosis of rare disease. It should be noted that, to date, there is no database or an official way of recording the number of cases. One of the quantitative criteria is the Card for the Person with a Rare Disease.
As the Directorate-General for Health (DGS) recently told the press, since 2014 there are 7,177 people with this card, a number that is significantly lower than the current estimate.
There have been many developments in medicine that have allowed, over the past decades, to evaluate, recognize and demystify the information on this subject. Currently, between 7 and 8 thousand rare diseases are registered, and it is possible to detect about 3,600 through laboratory analysis.
The objectives established by the International Consortium for Research on Rare Diseases (IRDiRC) determine that, by 2027, it will be possible to make the diagnosis of all the described rare diseases within a year, a thousand orphan drugs will be available (at the moment we have about 200) and there will be a broad knowledge of these diseases so that the action strategies are increasingly more comprehensive.
Brito Avô believes that Portugal “is a good example in this area”, alluding to the strategy implemented through the integrated approach of the Ministries of Health, Social Security and Education, which aims to respond to the health, social and educational needs of these patients. The objective of this strategy is to ensure that people with rare diseases have better quality and access to healthcare and treatment, based on the evidence that science has been producing, and greater speed and variety of social responses adapted to each case. The first step was the implementation of referral centres that provide differentiated, highly specialized care with no orphan drugs, specific training capacity for health professionals, organization of records and medical research, and integration in European knowledge networks, such as the European Reference Network (ERN).
Currently, in our country there are reference centres for eight areas of Rare Diseases. These centres work closely with patient associations (seen as the main recruiter of patients for clinical trials) in order to join forces in an attempt to improve the quality of life of those with a rare disease.
Brito Avô pointed out that about 80% of these diseases are genetic in nature and almost 50% are manifested in childhood. This type of disease is often serious and disabling, and responsible for 35% of infant mortality in the first year of life.
Dr Anabela Oliveira, as coordinator of the adult area of the Reference Centre for Hereditary Metabolic Diseases, warned of the importance of neonatal screening and the positive implications for public health. Neonatal screening is part of the National Early Diagnosis Programme and has existed since 1979. At that time, only two diseases were screened: phenylketonuria and congenital hypothyroidism. Today, it is possible to track about 24 hereditary metabolic diseases.
Anabela Oliveira also referred that “600 hereditary errors of metabolism” are known. It is “a type of disease that is not much talked about in the graduate and non-graduate training” of doctors.
The Reference Centre for Hereditary Metabolic Diseases was recognized in 2016 and has a multidisciplinary team, where nutrition and social action have not been neglected. It works in partnership with nationally renowned laboratories with extensive experience in this type of diseases. The Doctor Jacinto Magalhães Medical Genetics Centre, the Porto Hospital Centre, the Genetics Unit of the National Health Institute Doutor Ricardo Jorge and the Laboratory of Genetics at FMUL were particularly praised.
In turn, Isabel Conceição spoke about the work conducted at the Reference Centre for Family Paramyloidosis, which was officially recognized in 2015, but whose work dates back to the late 1980s. She highlighted that Portugal is the country in the world with the highest prevalence of Familial Amyloidotic Polyneuropathy (PAF), commonly known as Paramyloidosis, with 20% of cases worldwide in our country alone.
Nowadays, “Paramiloidosis starts to come out of the nomenclature a little or almost completely”, continued Isabel Conceição, “because most patients do not have Polyneuropathy. Interestingly, most patients have Cardiomyopathy. It is estimated that around 40 thousand patients worldwide have a cardiac form of hereditary amyloidosis”. She added that “the idea that we only have one mutation in Portugal is wrong and the picture has changed”.
As a “multi-systemic” disease, the Reference Centre for Familial Paramyloidosis monitors patients “across the circuit and specialties” (from Neurology and Genetics to Ophthalmology, Nephrology, Psychiatry, and Nutrition, among many others), also playing an important role in the training of young doctors, and assuming that same training and educational responsibility with patients and the general public. This reference centre has an open consultation and currently follows 400 patients, of whom 150 are asymptomatic.
Isabel Conceição was heavily involved in the scientific and clinical advances in response to Paramyloidosis and shared her experience with us. “The first proposed treatment was liver transplantation, which continues to be a therapeutic indication in the earliest stages of the disease, and it is gratifying that I went through all the stages: the stage when there was no type of therapy, the stage when liver transplantation was the only therapeutic option and the phase we live in today, which is the phase of development, ranging from protein stabilizers to the latest novelties of RNA silencers”, hoping to continue to offer“ more and better ”to patients.
Nutrition, particularly in metabolic diseases, plays a major role and in this e-Talks we discussed the importance of food in the control and treatment of these such unusual pathologies. Patrícia Nunes stated that nutritional monitoring is essential to ensure that the height-weight development of patients occurs in the most appropriate way.
The more than 20 years of experience in our hospital centre, whose work is closely linked to aminoacidopathies, in particular to phenylketonuria, allowed Patrícia Nunes to show that rare diseases are a constant challenge for nutritionists, who “must be very up to date on all nutritional issues and understand the habits and nutritional needs of patients”. “There is a very wide range of pathologies in which nutrition has a very significant weight and, at the moment, the hospital centre has 5 nutritionists specialized in this area”, a significant number that shows the importance attributed by CHULN to this problem. She also emphasised the importance of the Master Degree in Metabolic Diseases and Eating Behaviour offered by our faculty. "There are two students currently in this area and they have made an excellent contribution", concluded Patrícia Nunes.
The notable advances in genetic and molecular medicine over the past few years and the evolution of therapeutic experimentation models so important for the care of patients with a rare disease were also talked about.
Simão Rocha researches Angelman Syndrome, a neurogenic pathology that severely affects physical and intellectual development. There are 75 known cases in Portugal. Considering the importance of creating “pre-clinical models that allow drug testing in these diseases”, he explained the work he has been conducting in this field. “What we are doing in Professor Carmo Fonseca's laboratory at the iMM is, following having access to patients with Angelman - through doctor Sofia Duarte at Estefânia Hospital – to collect biological material and do a skin biopsy. From there, we managed to grow cells in the laboratory, and now we are able to transform these cells into the so-called stem cells. The great advantage of these cells, which are undifferentiated cells that came from patients, is that we are now able to differentiate them into cell types that we are interested in studying.
In the context of a disease like Angelman, a neurodevelopmental disease, we can, in the laboratory, transform these cells into neurons or even form three-dimensional structures in order to better understand the complexity of the disease”. Simão Rocha was hopeful with regard to this preclinical model, namely the possibility of being applied in other types of diseases. He noted, however, that the ongoing research work “does not treat current patients, but we hope that in the near future we can treat and even cure this type of disease”.
In view of such favourable advances, the next step reflects the interaction between the biomedical sciences and their practical medical application, which determines the true success in the treatment of the disease. As Brito Avô explained, “it is essential to transfer this knowledge to clinical and pharmacological/therapeutic activities, in order to identify how to treat the disease”.
There have been many clinical trials and treatments carried out over time and Patrícia Aguiar pointed out that it is precisely in the area of rare diseases that therapeutic development is most promising. “This is because the set of new therapies is very large and has allowed, in some diseases, to modify the natural disease in a very important way, turning diseases that were deadly at a very early age until a few years ago into chronic diseases that allow a very reasonable quality of life”.
Among others, Patrício Aguiar mentioned the enzyme replacement therapy created in the laboratory, adding that “the future in this type of disease will involve gene therapy, which is also a form of enzyme replacement”. Human trials for some genetic diseases are already underway. He also stressed “genomic edition” - “something unthinkable a few years ago” - as a new and more comprehensive therapeutic perspective to be developed in the future. In the spotlight are also home therapies and stem cell neurodegeneration to correct central nervous system problems, among other therapies that have been tested. "Novelties" included the significant advances in the study of the permeabilization of the blood-brain barrier to different forms of therapy. “We live in a time of transformation in the way we treat our patients. It is very gratifying and we are already changing the way these patients are treated”, he concluded.
At the end of the session, it was possible to unanimously understand that it is this interdisciplinary view of several areas that best allows to outline an effective action strategy in the face of Rare Diseases, which affect around 300 million people worldwide. The future looks auspicious and we are moving in the right direction, because each day is a new opportunity for evolution in Medicine and an incitement to hope for those who face, daily, the challenges of living with a rare disease.