Fabry disease

When the father (XY) is affected, he transmits his single X chromosome to his daughters but not to his sons, who receive the Y chromosome from the father. When the mother (XX) is affected, having two X chromosomes and only one affected, she has a 50% chance of transmitting either the healthy or the altered X chromosome to both daughters and sons. Women, having two X chromosomes, can have the non-affected chromosome partially compensate for the affected one. Therefore, they may present various clinical forms, ranging from mild to severe, and generally with later onset than in men. Men with classic mutations of Fabry disease usually present severe forms, with onset even in childhood or adolescence.

Approximately 1,000 different variants of the affected GLA gene are known. This explains why Fabry disease can manifest in diverse forms depending on the type of mutation (classic forms or late-onset/atypical forms).

It is a multisystemic disease (affecting the kidney, heart, nervous system, skin, eyes, among others) that requires multidisciplinary care. Multiple specialists need to work together.

Symptoms

• Peripheral nervous system involvement: Pain and discomfort in the hands and feet. With heat or walking, they may turn red and hurt (acroparesthesias).
• Small red raised spots (angiokeratomas): Non-contagious, usually appearing on the abdomen, genitals, thighs, and buttocks.
• Reduced sweating (hypohidrosis): Leads to poor heat tolerance.
• Flushing: Due to impaired temperature regulation.
• Exercise intolerance: Patients fatigue very quickly.
• Gastrointestinal manifestations: Abdominal pain from childhood, sometimes associated with diarrhea related to food intake; fatty meals worsen symptoms. Resemble irritable bowel syndrome.
• Cardiac involvement: Myocardial hypertrophy (enlarged heart) without apparent cause; arrhythmias (irregular heartbeat).
• Renal involvement: Decreased kidney function, protein loss in urine.
• Central nervous system involvement: Stroke. If a relatively young person has a stroke without a clear cause, Fabry disease should be considered.
• Hearing loss: Sudden or rapidly progressive.

Who is affected

It generally affects men more severely than women. X-linked inheritance means there are almost twice as many affected women as men, but variability in expression causes many women to remain undiagnosed. Classic mutations start in childhood, and boys may present symptoms as early as 3–4 years old, depending on the mutation type.

Diagnosis

Early diagnosis can be made through a blood test to determine enzymatic activity and genetic testing.

Depending on which organ is affected, Fabry disease may appear as different clinical problems. For kidney issues, the patient sees a nephrologist. Patients with arrhythmias may see a cardiologist. Pain may require a neurologist or rheumatologist, and skin lesions a dermatologist.

The disease usually begins with hand and foot pain, abdominal pain, fatigue, some skin lesions, and later kidney involvement in adolescence (albumin in the urine). It can also cause cardiomyopathy or left ventricular hypertrophy, detectable via echocardiography.

Symptoms appear progressively. Healthcare professionals must be aware of this possibility, detect it, and diagnose it in time.

Treatment

Fabry disease can be treated symptomatically with medications for pain, proteinuria, or arrhythmias. Additionally, there are specific treatments.

Since 2001, enzyme replacement therapy (ERT) has been available. This therapy addresses the deficient enzyme production. Through genetic engineering, the enzyme can be produced in the lab and administered intravenously every 15 days. The protein enters the cell and acts for several days, but because the body does not produce it, supplementation must continue.

ERT reduces the occurrence of severe complications and improves survival by an average of 20 years. For optimal therapeutic benefit, treatment should start before irreversible tissue damage occurs.

Recently, another treatment alternative has emerged: pharmacological chaperone therapy. If the gene mutation produces no protein, this therapy cannot be used. If a defective protein is produced, the molecule binds to it, modifying its structure and improving its activity in genetically responsive variants (20–30%).

At Vall d’Hebron Research Institute, studies are underway to improve intracellular transport and drug efficacy using nanoparticles, which facilitate delivery of the enzyme precisely to the required site.

Another treatment in development is gene therapy, which involves introducing a normal gene into the cell via a vector so that the cell can produce the enzyme normally and permanently. If successful, this would be a curative treatment.

Prevention

Expanded genetic testing helps study the family and detect affected individuals in early stages. Screening at-risk populations such as people with unexplained kidney disease, unexplained myocardial hypertrophy, early stroke, or sudden hearing loss is essential. Specialists in nephrology, cardiology, neurology, dermatology, ophthalmology, ENT, and other fields must consider Fabry disease, along with family history and clinical records, to detect it early and achieve optimal benefits.