Purpose: To determine if there is significant symptomatology in women with heterozygous ␣-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 ϭ 0.049); exercise intolerance, present in 83%, was associated with reduced maximal heart rate during exercise testing (P ϭ 0.0089). Women diagnosed via family history experienced more angina (P ϭ 0.035), decreased vibration sense (P ϭ 0.026), and had a worse percentage predicted FEF 25-75 (P ϭ 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. Genet Med 2007:9(1):34-45.

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