CASE REPORT A Novel ␣ -Galactosidase A Mutant (M42L) Identified in a Renal Variant of Fabry Disease David Rosenthal, MD, Yeong-Hau H. Lien, MD, PhD, Donna Lager, MD, Li-Wen Lai, PhD, Shuhua Shang, MD, Nelson Leung, MD, and Fernando C. Fervenza, MD, PhD ● A 65-year-old man presented to our institution for workup of proteinuria. His serum creatinine level was 1.7 mg (130␮mol/L), and he had proteinuria with protein of almost 5 g/24 h. Fabry disease was diagnosed by means of kidney biopsy and low serum and leukocyte levels of ␣ -galactosidase A. Review of his history, family history, physical examinations, and diagnostic studies did not show other findings typical of this disease. His renal functi continued to decline, and he eventually underwent a living unrelated renal transplantation 5 years later. Three y aftertransplantation, his creatinine level is 1.7 mg/dL (130 ␮mol/L),and corrected iothalamate clearance is 53 mL/min/1.73 m 2 . Genetic studies showed that he has a novel missense mutation (M42L) in exon 1. Methionine at codon 42 is highly conserved in eukaryotic ␣ -galactosidase A orthologues. This genotype predicts a minor misfolding of ␣ -galactosidase A because of a small difference in hydrophobicity between methionine and leucine. His mutation resulted in a very low, but detectable, serum level of ␣ -galactosidase A (0.002 U/L; normal range, 0.016 to 0.2 U/L). Cases of Fabry disease that present with predominantly renal manifestations are rare and require a h index of suspicion for diagnosis. Because treatment for Fabry disease recently has become available, it is import for clinicians to be aware of this disease and pursue the diagnosis in cases of otherwise unexplained renal dysfunction. Am J Kidney Dis 44:E85-E89. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Fabry disease; ␣ -galactosidase A; genotype; phenotype; mutation analysis. F ABRY DISEASE is a rare X-linked recessive glycosphingolipid storage disease caused by mutations in the ␣ -galactosidase A gene. 1 ␣ -Galac- tosidase A is a lysosomal enzyme essential for removal of globotriaosylceramide from cells. In the absence of this enzyme, globotriaosylceramide and digalactosylceramide accumulate mainly in endo- thelial cells from renal, cardiac, and nervous sys- tem tissue. These substances also accumulate in renalepithelial cells,neurons, myocardial cells, and vascular smooth muscle cells. Removal of 3 hexose residues from globotriaosylceramide is es- sential for lysosomal processing of this molecule. Mostpatients with classic Fabry disease have a complete lack of enzyme function of ␣ -galactosi- dase A and present with a combination of cardiac, ophthalmological, neurological, dermatological, and renal problems. Manifestations include cardiomy- opathy, valvular heart disease, small macules and papules in the bathing trunk region (angiokerato- mas), episodic pain in a stocking-glove distribution (acroparesthesias), hypohidrosis, cornea verticil- lata, cerebrovascular disease, and proteinuria with chronic renal failure. 2 Many different mutations of the ␣ -galactosi- dase gene have been reported. 3 Patientswith mutations that leave them with some residual enzyme function may have only 1 or 2 manifesta- tions and are referred to as oligosymptomatic. Very few of these cases have been reported in the literature. Most of these patients have had at least 1 other manifestation of Fabry disease, such as left ventricular (LV) hypertrophy 4-6 or angiokera- tomas. 7 We report a case of a renal variantof Fabry disease caused by a new missense muta- tion in the ␣ -galactosidase A gene. CASE REPORT A 65-year-old white man was referred to our institution for evaluation of long-standing proteinuria. He first became proteinuric approximately 20 years ago, butno cause had ever been discovered. He did not have a personal or family history of kidney disease or diabetes. His father died at age 106,and his mother died at age 86. He had hypertension, which had been diagnosed 7 years earlier and treated with an From the Departments of Medicine; and Pathology, Mayo Clinic and Foundation, Rochester, MN; and the University of Arizona, Tucson, AZ. Received May 3, 2004; accepted in revised form July 1, 2004. The genetic diagnosis of Fabry disease was supported in part by a grant from Dialysis Clinic Inc, a nonprofit organi- zation (Y.-H.H.L. and L.-W.L.). Addressreprintrequests to Fernando Fervenza, MD, PhD, Division ofNephrology and Hypertension, Mayo Clinic,200 FirstSt SW,Rochester, MN 55905. E-mail: fervenza.fernando@mayo.edu © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4405-0028$30.00/0 doi:10.1053/j.ajkd.2004.07.018 American Journal of Kidney Diseases, Vol 44, No 5 (November), 2004: E85-E89 e85