Fabry's disease. All about this rare condition of difficult diagnosis

Is the incidence in Portugal and the world known? 

Worldwide, prevalence data depend heavily on the series evaluated. Although rare, there are studies that say you're underrated. In Portugal we have to highlight the merit and differentiating role of all the work that has been developed over the past few years by Professor Dr. Olga Azevedo and team, having been discovered in Guimarães, the “founding effect” of DF associated with a certain mutation. In this context, a very interesting work involving consultation of historical archives of Guimarães was developed, and a woman who lived more than 400 years ago was identified as the precursor of this disease in that area for most of the families identified, which was transmitted to the following generations. With the high emigration of the Portuguese population, we find this kind of mutation also elsewhere in the world. 
When we analyze the prevalence of this disease in patients with, for example, hypertrophic cardiomyopathy (heart with the walls “grossed”), we talk about a prevalence of around 0.9%. On the other hand, for example, in Guimarães, in a study conducted in 150 patients with hypertrophic cardiomyopathy, more than 16% had this disease, which is related to the previously mentioned founding effect.
In Guimarães there is also the Reference Center for Lysosome Overload Diseases, which is one of the largest European centers to follow patients with PD.

Does the fact that it is a genetic disease make it also hereditary? 

Fabry's disease is a hereditary genetic disease linked to X chromosome. This means, for example, that a man with the disease (as he has an X chromosome and a Y chromosome) always transmits the mutation to his daughters (through the X chromosome) and never to his children, because they transmit the Y chromosome. A carrier woman is 50% likely to transmit the mutation to a child or daughter (the woman has two X chromosomes). Therefore, it is very important in the assessment of patients with PD to perform the study and family screening, which allows the identification of other family members who may also be carriers.

What are the first symptoms to which it is important to be attentive?

Fabry’s disease may have an expression/presentation called “classic” or “late onset”, the latter being more frequent. This type of “expression” has an impact on the type of signs and symptoms that arise, as well as on the age of presentation. The expression/presentation “classical” presents signs and symptoms that may already appear in childhood. For example, eye and skin changes, abdominal pain, severe pain in hands and feet, intolerance to heat or exercise, deafness; throughout life it can also manifest with heart and kidney disease, etc. Patients with “late onset” expression have manifestations especially in adulthood. Often, these may predominantly involve an organ, such as the heart, manifesting with hypertrophic cardiomyopathy, arrhythmias (may also present in other ways, such as kidney disease, stroke, etc.).

Why is the diagnosis usually difficult or late?

The diagnosis may be difficult or late for different reasons, including the lack of adequate/ sufficient knowledge of the disease. Also because some signs and symptoms may be nonspecific and confused with other causes, namely less rare and better known. In the expression “classic”, with earlier onset of symptoms, as in childhood, these may be confused with infectious, rheumatologic, gastrointestinal diseases. So here it is very important to know the disease so that you can recognize it because, when it is a rare disease, it can become a little forgotten and unknown, in general. It is therefore important to promote their knowledge and dissemination. We can only diagnose if we know and think about the disease. And this disease has specific treatment, so the correct diagnosis is really relevant.

Can it be confused with other diseases?

Yes! And patients can go years without definitive diagnosis. There is more information, scientific documentation, allowing greater knowledge of rare diseases, such as PD, but there is still a way to be done.

What is the impact of diagnosis on the lives of these patients? 

Having a diagnosis is very important to patients because they will understand why they complain. The diagnosis will also allow a more appropriate follow-up, including in multidisciplinary consultations, with the support of different specialties (which is what is recommended). In this case, it also allows the screening of other family members. And it allows, of course, a more appropriate treatment, allowing access to specific treatment for the disease, whenever there is indication. This is all very positive. 
We must also consider the negative impact. It is a chronic disease with genetic transmission that will imply chronic follow-up, which is reflected in the management of the professional and personal life of each person. Patients must undergo different visits, different complementary diagnostic tests and, where indicated, undergo specific treatment in addition to the other supportive treatment they may need. They have to deal with a complex, multisystemic chronic disease that usually affects different organs with a family component, which has an important emotional impact.

How is diagnosis and medical follow-up done?

When there is suspicion, signs and warning symptoms (with clinical data, tests with suggestive changes) an evaluation is performed with analyses that allow you to see the activity of this enzyme, if it is not working well, and a genetic study that will allow you to identify if there is a change that causes and explains the disease. After that, the patient is followed in multidisciplinary consultation: cardiology (a dedicated cardiology consultation, cardiomyopathies) and other specialties (neurology, psychiatry, otorhinolaryngology, ophthalmology, etc....), being submitted to different tests and evaluations, according to the established and necessary in each case. And the periodicity of these consultations will also depend on the evolution of the disease and the involvement by the patient. Monitoring is done in an organized, systematic and multidisciplinary manner. When diagnosed, depending on the case, patients may be proposed for evaluation by the Reference Centers, within the decision whether there is an indication for specific disease therapy. The diagnosis can also be made in the context of the screening of relatives of identified patients.

What psychological or social challenges can they face? 

These challenges depend on several factors, such as how each person deals with the disease, but also the degree of involvement/ evolution of the disease. In psychological terms, patients may report complaints compatible with depression, anxiety, fatigue; also feeling misunderstanding, such as being associated with complaints of pain, since many of their symptoms may be disabling and not “visible”. There is also an impact on professional life, on the time spent on appointments, hospital visits and treatments. And then, of course, the possibility of transmission to the children. All this adds to the impact of being a rare disease that, often due to ignorance, can be devalued by peers. 
Each person deals with the disease in their own way, and it is very important to have access to support from psychology and psychiatry, and this is recommended in the evaluation and monitoring of these patients, because it is effectively necessary and cannot be devalued.

How does the disease evolve over time? What organs are most affected and what complications can it cause?

Over time, worsening organ dysfunction may develop, particularly if the disease is not treated. The evolution and manifestations will also depend if the disease is of a “classic” type or “late onset”, as mentioned. Hence the importance of an early diagnosis, which may allow timely treatment. When the diagnosis takes place at a later stage the expected improvement will not be so good and there may already be irreversible damage that may continue to progress/progress.

Is there any treatment? 

Yes, there is supportive treatment and specific treatment. Support treatment allows managing the comorbidities and complications associated with the disease, such as the treatment of heart failure, implantation of medical devices such as pacemakers, among others. Specific treatment depends on each case; it may be enzyme replacement, intravenous and involves infusion of a medicinal product; there is additional oral treatment. The beginning and choice of treatment depend on an adequate evaluation, so as to understand whether it is indicated and what is best for each case. The specific treatment currently available is a chronic treatment, not allowing the disease to be cured. But in this field there is scientific research to be developed.

Is it possible to have this disease and not know?

The manifestations are often attributed to other causes, both in later manifestations and in manifestations still in childhood, which leads to the possibility of living several years without diagnosis. Therefore, there may be people who have Fabry's disease and do not know it, which is why it is considered underdiagnosed in terms of prevalence.

What are the main obstacles these patients face? 

The delay in diagnosis, the progression of the disease, and the need for a follow-up to life (the psychological impact, the comorbidities, the impact of work); the misunderstanding, because it is a rare disease, the lack of knowledge, both on the part of the scientific community (in general, of course), and of the population, on the global. There is still room for improvement in diagnosis, which may allow for more patients to be identified and at earlier stages. 

Being a rare disease, are doctors aware of this condition?

There is still an important way to go, although there is more and more alertness and knowledge about the disease, even by the clinical investigation that has emerged and dissemination of it. Complementary diagnostic tests, increasingly available, may sometimes raise suspicion or this diagnosis hypothesis. But effectively, there's still room for improvement. And we see this in our clinical practice, when we received patients at our consultation, in which we eventually diagnosed this disease, and we see that there were signs and symptoms previously, which could lead to the investigation of this diagnosis.

What can be done to make it a disease better known to people?

It is necessary to disseminate and continue to bet on medical education. There are already several initiatives in this field, for example, by the Portuguese Society of Cardiology, particularly by the Myocardial and Pericardial Diseases Study Group. Professor Olga Azevedo herself, with all the history in this area, as well as in the field of cardiomyopathies, has done several training and awareness actions with colleagues, including in primary health care. It is also very important to have differentiated consultations of cardiomyopathies, which have a systematized evaluation, of which the study and the detection of this disease is part, in the appropriate context. It is also important to multidisciplinary and collaboration with other specialties in this context.
There should also be appropriate dissemination to the population, which is developed, for example, by patient associations in different areas of the world.

Are there new therapies in research or promising clinical trials?

Yes, there are new lines of treatment under investigation, with promising trials, such as so-called “substrate reduction” therapy (which means reducing the production of products that accumulate due to this disease), and genetic therapy, which tries to correct the deficiency of this enzyme, notably through the so-called virus-associated vectors. There are promising new lines of investigation. But let's not forget that we can only treat what we diagnose. Therefore, it is important to continue investing in the dissemination of this disease, not forgetting the population, thus promoting its recognition and diagnosis.