A Novel Frameshift Mutation of Galactosidase-alpha in Fabry Disease Restricted to Dermatologic Manifestations
A 28-year-old Asian male presented with a 4-year history of small, raised, reddish-purple maculopapules affecting his genital area and lower trunk. He was otherwise well, with no past medical history with the exception of hypohidrosis since childhood. There was no family history of kidney failure, heart disease, stroke, or other signs or symptoms of Fabry disease.\nOn examination, skin lesions tended to increase in number and size with age, and were clustered prominently and densely around the penis and scrotum (). Tiny macules were peppered over the patient's lower abdomen and back ().\nRenal function panel, including glomerular infiltrate rate and urine microalbumin, were normal. Electrocardiogram and echography also showed normal cardiac chamber size and wall thickness. In addition, no abnormalities were found on brain magnetic resonance imaging or neurologic examination. There were no aneurysmal dilatations of the conjunctival vessels or diffuse corneal opacities (i.e., corneal verticillata) on ophthalmologic investigation.\nHistologic examination of skin biopsies from the left side of the abdomen and penile shaft revealed a moderate hyperkeratosis with dilated blood vessels filled with erythrocytes in the epidermis (). In the upper dermis, enormously dilated vessels were present, some surrounded by epithelial sprouts. A moderate lymphohistiocytic infiltrate was observed. These findings were consistent with a diagnosis of angiokeratoma.\nThe clinical symptoms and histological findings described above suggested the possibility of Fabry disease. The appropriate biochemical examination required to confirm the diagnosis was made through demonstration of deficient α-galactosidase A activity and identification of a pathogenic mutation of GLA. With the addition of N-acetylgalactosamine, the activity of α-galactosidase B was eliminated. Enzyme activity of the patient, as determined by fluorescence of 4-methylumbelliferryl, confirmed a GLA enzyme deficiency with an average of 0.00 nmole/hr/mg. Furthermore, in order to determine whether GLA was mutated, polymerase chain reaction sequencing was done with the use of the DNA separated from peripheral blood. Analysis of the DNA sequence for the exon and exon-intron boundaries of seven GLA genes revealed a c.182_183ins(GA) (pAsp61GlufsX32) frameshift mutation at exon1.\nDue to the patient's personal reasons, genetic counseling and evaluation of family members were not performed, but the family history gave no suspicion of Fabry disease. Enzyme replacement therapy (ERT) is currently being administered, and symptoms are being managed through constant observation of progress.