30/04/2025

On the occasion of Fabry disease awareness month, we close the month of April by talking to Dr. Javier Limeres, cardiologist at the Vall d'Hebron Hospital, specialist in this rare lysosomal pathology.

According to Orphanet, Fabry disease is a rare multisystemic lysosomal disease of genetic origin characterized by specific cutaneous (angiokeratoma), neurological (pain), renal (proteinuria, chronic renal failure), cardiovascular (cardiomyopathy, arrhythmia), cochleovestibular and cerebrovascular (transient ischemic attacks, strokes) manifestations. The phenotypic expression is highly variable, the age of onset ranges from infancy to adulthood and the clinical expression in females depends on the degree of inactivation of the X chromosome.

From a historical perspective, Fabry disease has an interesting history, as two physicians, surnamed Anderson and Fabry respectively, described it at about the same time. "One of the physicians, Anderson, described it in the English language, while in Europe it is more commonly known as Fabry disease," explains Dr. Limeres. Although they both made their descriptions simultaneously, their focus was mainly on the more severe phenotypes, which we know today as the classical phenotypes, and the late ones (the most common within this low-prevalence disease) were described a posteriori. In the early cases, the clinical manifestations are much more aggressive, with a higher mortality compared to the late forms. The initial symptoms were closely linked to the skin, with skin lesions in areas such as the swimsuit, groin and armpits. However, "these physicians did not yet know that it was a lysosomal disease," an aspect that would later be discovered with the advance of microscopy and biochemical techniques, says the doctor.

Over time, "it was discovered that some patients did not present the classic symptoms and their manifestations were much later, affecting specific organs, without necessarily involving the skin". In this sense, patients with Fabry disease currently have greater involvement in organs such as the brain, heart and kidney, "which has a determining influence on the prognosis of the disease," he adds.

How it is diagnosed

One of the main challenges in diagnosing Fabry disease remains, according to Dr. Limeres, the difficulty in suspecting it because of its rarity and, in general, the lack of awareness among physicians who are unfamiliar with it. "It is a rare disease and, as physicians, we often don't think of it when we are confronted with symptoms that could be related." An example of this is when a child presents with diarrhea or abdominal pain, which can easily be interpreted as gastroenteritis or some other more common illness. This challenge also presents itself to cardiologists, who sometimes come across patients who have ventricular hypertrophy, which could suggest hypertrophic cardiomyopathy, and when they perform a genetic study, "they suddenly find a diagnostic mutation for Fabry," the doctor explains.

Therefore, as in all rare diseases, early diagnosis is essential and, although there are screening strategies in certain patient niches, such as those with advanced renal failure or patients on dialysis, "mass screening has not yet been validated in the general population, as is the case with other diseases". In this case, screening is done by analysis of the enzymatic activity of GLA (protein altered in Fabry disease) or by a genetic study with a very conclusive result.

In this regard, Dr. Limeres also talks about advances in precisely this detection of the disease through genetic studies, which are becoming increasingly cheaper. "In the future, it is likely that genetic studies will be so cheap that we will be able to sequence the genome or exome of children and detect variations associated with Fabry." However, despite the advances, "there will always remain the uncertainty of whether or not a detected variant has the potential to cause the disease."

Symptomatology of Fabry

Fabry disease is X-linked, which implies that "men have a greater probability of having manifestations of the disease, since they have only one X chromosome, while women, having two, can be carriers and not present symptoms, depending on whether the healthy or diseased X chromosome is expressed in their cells," explains Javier.

"When a patient is diagnosed with Fabry, it is essential that he or she be evaluated by a team that includes cardiologists, nephrologists, eye specialists and other specialists."

In the case of men, the disease is almost always more severe, since all their tissues are involved, as 100% of their cells are affected.

Fabry disease, as Dr. Limeres points out, is a systemic disease that affects several organs and is not limited to cardiac problems. Therefore, its approach must be multidisciplinary. "When someone diagnoses a patient with Fabry, it is essential that he or she be evaluated by a team that includes cardiologists, nephrologists, eye specialists and other specialists." In addition, in classic phenotypes, especially in males, pediatric care is crucial, since "deposits of the disease can begin to occur even before birth." "If diagnosed and treatment is started early, it is possible to slow down long-term damage and avoid serious complications."

In addition to the classic symptoms such as abdominal pain, skin and eye manifestations, and cardiac problems, "there are rare manifestations of the disease, but they should not be considered in isolation as indicative of Fabry". For example, abdominal pain in Fabry is not limited to gastric symptoms, but "can be colic that is exacerbated at certain times of the year, accompanied by diarrhea and food intolerance". However, unlike what happens with other diseases, "there is no direct damage to organs such as the intestine or the stomach", but rather a systemic alteration that affects all the cells of the body and causes pain that is sometimes totally disabling.

Treatment and the future of patients

The treatment of Fabry disease, according to Dr. Limeres, has advanced significantly in recent years. Patients diagnosed early have a better quality of life. "In addition to Fabry-specific therapy, patients also require treatment for comorbidities, such as heart failure or gastrointestinal problems."

"Therapeutic advances could allow patients to produce the needed enzyme on their own, which could reduce or eliminate the need for replacement therapies."

 Treatment is essential to improve the quality of life of patients, who, with early diagnosis and appropriate treatment, can "lead a normal life and at least partially halt the progression of the disease". However, treatment is complex and can sometimes require adjustments, as "not all patients respond equally to the available therapies".

In the future, new molecules and treatments, such as gene therapy, offer hope. In this sense, Dr. Limeres points out that "advances in this type of therapy could allow patients to produce the necessary enzyme on their own, which could reduce or eliminate the need for replacement therapies". However, he emphasizes the value of research and the imperative need to continue investing in it "these treatments still need to be further investigated and validated before they can be implemented on a massive scale," concludes the doctor.