Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life

Purpose: To determine if there is significant symptomatology in women with heterozygous alpha-galactosidase mutations. Methods: Data from medical records of the 44 heterozygous females followed at Cedars-Sinai Medical Center were compiled and analyzed for symptoms of Fabry disease. Quality of life data were also analyzed. Results: Seventy-six percent were referred due to an affected male relative; 76% reported acroparesthesias as their first symptom. A mean of 15.7 years elapsed from onset of first symptoms to the diagnosis. Quality of life, measured by the SF-36 survey, was globally reduced. Pain affected mood and enjoyment of life. Central/peripheral nervous, cardiopulmonary, and renal system manifestations of Fabry disease were present far above that predicted for random X-inactivation of the normal allele. Fatigue, present in 59%, was associated with reduced maximum oxygen consumption (P = 0.049); exercise intolerance, present in 83%, was associated with reduced maximal heart rate during exercise testing (P = 0.0089). Women diagnosed via family history experienced more angina (P = 0.035), decreased vibration sense (P = 0.026), and had a worse percentage predicted FEF25-75, (P = 0.037) compared to women diagnosed because of symptoms. Conclusions: This study indicates that the asymptomatic female carrier of Fabry disease is the exception, not the rule: heterozygotes suffer from significant multisystemic disease and reduced quality of life and must be monitored and treated accordingly.