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 doctors—surnamed Anderson and Fabry, respectively—described it at roughly the same time. “One of the doctors, Anderson, described it in English, while in Europe it is better known as Fabry disease,” explains Dr. Limeres. Although both provided their descriptions simultaneously, their focus was primarily on the more severe phenotypes—which we now know as the classic phenotypes—while the late-onset forms (the most common within this low-prevalence disease) were described later. In the early cases, the clinical manifestations are much more aggressive, with a higher mortality rate compared to the late-onset forms. The initial symptoms were closely linked to the skin, with skin lesions in areas such as the groin, armpits, and where swimwear is worn. However, “these doctors did not yet know that it was a lysosomal disease,” a fact that would later be discovered with advances in microscopy and biochemical techniques, the doctor notes.

Over time, “it was discovered that some patients did not exhibit the classic symptoms and that their manifestations appeared much later, affecting specific organs without necessarily involving the skin.” In this regard, patients with Fabry disease today experience greater involvement of organs such as the brain, heart, and kidneys, “which has a decisive impact on the disease’s prognosis,” he adds.

How it is diagnosed

According to Dr. Limeres, one of the main challenges in diagnosing Fabry disease remains the difficulty in suspecting it due to its rarity and, in general, a lack of awareness among doctors who are not familiar with it. “It is a rare disease, and as doctors, we often don’t think of it when we encounter symptoms that could be related.” An example of this is when a child presents with diarrhea or abdominal pain, which can easily be misdiagnosed as gastroenteritis or some other more common condition. This challenge also arises for cardiologists, who sometimes encounter patients with ventricular hypertrophy—which could suggest hypertrophic cardiomyopathy—and upon conducting genetic testing, “suddenly find a mutation diagnostic for Fabry,” the doctor explains.

For this reason, and as with all rare diseases, early diagnosis is essential; however, although screening strategies exist for certain patient subgroups—such as those with advanced kidney failure or patients on dialysis—“mass screening of the general population has not yet been validated, as is the case with other diseases.” In this case, screening is performed by analyzing GLA enzyme activity (a protein that is altered in Fabry disease) or through genetic testing, which yields very conclusive results.

In this regard, Dr. Limeres also discusses advances in the detection of this disease through genetic testing, which is becoming increasingly affordable. “In the future, genetic testing will likely be so inexpensive that we’ll be able to sequence children’s genomes or exomes and detect variations associated with Fabry disease.” However, despite these advances, “there will always be uncertainty as to whether or not a detected variant has the potential to cause the disease.”

Symptomatology of Fabry

Fabry disease is X-linked, which means that “men are more likely to develop symptoms of the disease, since they have only one X chromosome, while women, who have two, can be carriers and remain asymptomatic, depending on whether the healthy or affected X chromosome is expressed in their cells,” explains Javier.

“When a patient is diagnosed with Fabry disease, it is essential that he or she be evaluated by a team that includes cardiologists, nephrologists, ophthalmologists, 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 disorder that affects various organs and is not limited to heart problems. Therefore, its management must be multidisciplinary. “When a patient is diagnosed with Fabry disease, it is essential that they be evaluated by a team that includes cardiologists, nephrologists, ophthalmologists, and other specialists.” Furthermore, in classic phenotypes—especially in males—pediatric care is crucial, since “disease deposits can begin to form even before birth.” “If the disease is diagnosed and treatment is started early, it is possible to slow long-term damage and prevent serious complications.”

In addition to classic symptoms such as abdominal pain, skin and eye manifestations, and heart problems, “there are rare manifestations of the disease, but they should not be considered in isolation as indicative of Fabry disease.” For example, abdominal pain in Fabry disease is not limited to gastrointestinal symptoms; rather, “it can manifest as colic that worsens at certain times of the year, accompanied by diarrhea and food intolerance.” However, unlike what occurs with other diseases, “there is no direct damage to organs such as the intestine or stomach,” but rather a systemic disorder that affects all the cells in the body and causes pain that is sometimes completely debilitating.

Treatment and the future of patients

According to Dr. Limeres, treatment for Fabry disease 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 enable patients to produce the necessary enzyme on their own, which could reduce or eliminate the need for replacement therapies.”

 Treatment is essential for improving patients’ quality of life; with early diagnosis and appropriate treatment, they can “lead a normal life and at least partially slow the progression of the disease.” However, treatment is complex and may sometimes require adjustments, since “not all patients respond equally to the available therapies.”

In the future, new molecules and treatments, such as gene therapy, offer hope. In this regard, Dr. Limeres notes that “advances in these types of therapies could enable patients to produce the necessary enzyme on their own, which could reduce or eliminate the need for replacement therapies.” However, he emphasizes the importance of research and the imperative need to continue investing in it: “We must continue to research and validate these treatments before implementing them on a large scale,” the doctor concludes.