Cases of Patients with E66Q Mutation Manifesting Zebra Bodies in Various Organs

Introduction: Fabry disease is a X-linked inherited disorder caused by mutations in the alpha-galactosidase A (GLA) gene, leading to the accumulation of globotriaosylceramide (Gb3) in various organs. The accumulation of Gb3 results in dysfunction of these organs. Although patients with the E66Q mutation have reduced GLA enzyme activity, this mutation is considered a functional polymorphism because Gb3 accumulation is not observed in any organs. We report here cases with the E66Q mutation in which histopathological examination revealed zebra bodies in various organs. Case Description: A 54-year-old woman was found to have the E66Q mutation from our previous Fabry disease screening study on hemodialysis patients at the age of 46. She initiated hemodialysis therapy at the age of 34, despite her young age, and suffered a cerebral infarction at the age of 44. She also had left ventricular hypertrophy and mild systolic dysfunction. A pathological specimen obtained during cataract surgery showed zebra bodies in the lens epithelial cells. A 34-year-old man, the son of the aforementioned patient, was also found to have the same genetic abnormality (E66Q mutation) at the age of 19 years during a family history survey. He was admitted to our hospital at the age of 33 years for the creation of an arteriovenous (AV) fistula due to progressive deterioration of kidney function. The vascular tissue obtained during the AV fistula surgery showed zebra bodies in both arteries and veins. A myocardial biopsy was performed at the age of 34 years to investigate left ventricular hypertrophy. Optical microscope images showed scattered vacuolar degeneration in cardiomyocytes, and electron microscope images showed zebra bodies in cardiomyocytes. Both patients received enzyme replacement therapy after diagnosis, which improved clinical symptoms such as limb pain and chest pain, as well as laboratory findings such as left ventricular mass and coronary flow reserve. Discussion: Although known reports suggest that patients with the E66Q mutation do not show tissue Gb3 accumulation, our findings otherwise. These patients exhibited zebra bodies in multiple organs, suggesting Gb3 accumulation. Therefore, we believe there is a possibility that E66Q may not be a functional polymorphism but a pathogenic mutation. Consequently, we suggest that the classification of E66Q should be carefully reconsidered.