Fabry disease is a rare, inherited disorder caused by a deficiency of the alpha-galactosidase A enzyme, leading to the accumulation of globotriaosylceramide (Gb3) in cells throughout the body. While historically considered a disease primarily affecting males, females are also affected, often presenting with diverse and variable symptoms. Understanding Fabry disease in females is important for timely recognition and appropriate care.
Understanding the Genetic Basis
Fabry disease originates from a mutation in the GLA gene, located on the X chromosome. This gene provides instructions for making the alpha-galactosidase A enzyme. Since females possess two X chromosomes, their genetic makeup introduces a unique aspect to how the disease manifests.
X-chromosome inactivation, also known as Lyonization, largely influences the variability seen in females. During early embryonic development, one of the two X chromosomes in each cell is randomly silenced. This random inactivation means some cells may predominantly express the healthy GLA gene, while others primarily express the mutated gene. This leads to varying levels of functional enzyme across different tissues and organs.
Consequently, females can experience a wide range of disease severity, from asymptomatic to severe manifestations, depending on which X chromosome is active in their cells. A female with Fabry disease has a 50% probability of passing the mutated GLA gene to each of her children, regardless of the child’s sex. Daughters who inherit the mutated gene will be affected. Sons who inherit the mutated gene will also be affected, typically with more severe symptoms due to having only one X chromosome.
Recognizing the Variable Symptoms
Females with Fabry disease exhibit a wide array of symptoms, often with variable onset, progression, and severity compared to males. Neurological manifestations include burning pain in the hands and feet (acroparesthesias), which may be triggered by exercise, fever, or stress.
Some females also report chronic neuropathic pain, headaches, or an increased risk of strokes and transient ischemic attacks (TIAs) at younger ages. Cardiac involvement is common, ranging from left ventricular hypertrophy (thickened heart muscle) to arrhythmias (irregular heartbeats). Valvular abnormalities, such as mitral valve prolapse, may also be observed.
Renal complications often begin with proteinuria (protein in the urine), which can progress to chronic kidney disease. Dermatological signs include angiokeratomas (small, dark red or purple spots), though these are less prevalent in females than in males.
Reduced or absent sweating (hypohidrosis or anhidrosis) can lead to heat intolerance. Gastrointestinal symptoms are frequently reported, including abdominal pain, diarrhea, nausea, and vomiting.
Other manifestations include fatigue, hearing loss, tinnitus, vertigo, and cornea verticillata, a whorl-like pattern in the cornea.
Diagnosis and Management
Diagnosing Fabry disease in females presents a significant challenge due to variable symptom presentation and unreliable enzyme activity tests. While males typically show very low or absent alpha-galactosidase A enzyme levels, females, due to X-inactivation, can have enzyme levels within the normal range, even if affected. This often leads to delayed or missed diagnoses. Therefore, a definitive diagnosis relies on genetic testing of the GLA gene to identify specific mutations. A thorough review of family history, looking for patterns of unexplained kidney disease, heart problems, or strokes, is also an important diagnostic step.
Management strategies for Fabry disease in females aim to slow disease progression and alleviate symptoms. Enzyme Replacement Therapy (ERT) involves intravenously administering a recombinant form of the alpha-galactosidase A enzyme. Chaperone therapy is another option for individuals with specific GLA gene mutations; this oral medication helps the body’s own mutated enzyme fold correctly so it can function more effectively.
Symptomatic management addresses specific manifestations such as pain, kidney issues, and cardiac complications through various medications and interventions. Given the multi-systemic nature of Fabry disease, a multidisciplinary care team, including nephrologists, cardiologists, neurologists, and other specialists, is often needed to provide comprehensive care.
Regular monitoring through clinical assessments, laboratory tests, and imaging studies helps track disease progression and allows for timely adjustments to treatment. Supporting overall quality of life, including addressing fatigue and managing daily challenges, remains a continuous focus of care.