Fabry disease is a rare, inherited lysosomal storage disorder where the body lacks sufficient functional alpha-galactosidase A (alpha-GAL) enzyme. This enzyme deficiency leads to the progressive accumulation of a fatty substance called globotriaosylceramide (Gb3) within cells and tissues. The X-linked condition means the gene is on the X chromosome, and its manifestations can differ significantly among affected individuals, including females who can experience substantial medical problems. The buildup of Gb3 over time damages blood vessels and tissues, potentially leading to serious complications in multiple organ systems.
Neurological and Pain Manifestations
Individuals with Fabry disease often experience a characteristic pain known as acroparesthesia, typically burning, tingling, or shooting sensations in the hands and feet. These painful episodes vary from mild to debilitating, lasting minutes to several days. Pain attacks are frequently triggered by factors like fever, strenuous physical activity, emotional stress, or temperature changes.
A common symptom is impaired sweating, referred to as hypohidrosis (reduced) or anhidrosis (absent). This reduced sweating capacity leads to heat intolerance and difficulty regulating body temperature, sometimes resulting in frequent fevers. The sweating abnormalities are believed to be caused by Gb3 accumulation in sweat glands and nerve cell damage affecting their function.
Skin, Eye, and Hearing Symptoms
Fabry disease can manifest on the skin as angiokeratomas: small, dark red to purplish, slightly raised lesions. These lesions often appear in clusters, commonly found on the lower trunk, buttocks, upper thighs, belly button, elbows, and knees. These skin lesions are usually not large and may be mistaken for general rashes, often leading to delayed identification.
A distinctive eye finding in Fabry disease is corneal verticillata, characterized by pale gray, brownish, or yellowish streaks or a whorl-like pattern in the cornea. This corneal opacity is present in over 90% of Fabry disease patients, including a mild form in most children, and is particularly prominent in female carriers. Although a strong diagnostic indicator, it rarely affects vision.
Other eye abnormalities include spoke-like cataracts, known as Fabry cataracts, which are opacities on the lens. These cataracts appear as linear whitish opacities near the posterior capsule with a radial distribution. Beyond visual symptoms, individuals with Fabry disease may also experience hearing issues such as tinnitus (a ringing sensation in the ears) and progressive high-frequency hearing loss.
Major Organ System Involvement
Fabry disease can severely affect the kidneys, with early signs including proteinuria (protein in the urine). As the disease progresses, kidney function can decline, leading to chronic kidney disease and eventually kidney failure, often necessitating dialysis or a kidney transplant. The accumulation of Gb3 in kidney cells contributes to this progressive damage.
Cardiac complications are a significant concern, frequently developing as patients age. These include hypertrophic cardiomyopathy (a thickening of the heart muscle), arrhythmias (irregular heartbeats), and valvular heart disease, such as problems with the mitral valve. Such heart issues can lead to an enlarged heart, heart attacks, and heart failure.
Cerebrovascular manifestations are a serious aspect of Fabry disease, with individuals at risk for transient ischemic attacks (TIAs), often called mini-strokes, and full strokes, sometimes occurring at unusually young ages. These neurological events stem from damage to blood vessels in the brain due to Gb3 accumulation. The disease can also lead to nerve damage, which may manifest as weakness, headaches, or dizziness.
The gastrointestinal system is commonly affected, with symptoms appearing early in life for some individuals. These can include chronic abdominal pain, nausea, vomiting, abdominal bloating, and alternating episodes of diarrhea and constipation. These gastrointestinal issues are believed to be related to impaired intestinal motility.