Case report: is low α-Gal enzyme activity suffcient to establish the diagnosis of Fabry disease?

Abstract

Fabry disease is an X-linked lysosomal storage disease due to alpha-galactosidase A (α-Gal A) deficient activity which leads to the accumulation of glucoesphingolipids, such as globotriaosilceramide. There are over 700 known mutations of the enzyme gene, and most of them cause Fabry Disease. This case report describes a hemodialysis patient with a rare and controversial GLA gene mutation, the D313Y. The medecial investigation confirmed that D313Y is an alpha-galactosidase A sequence variant that causes pseudo deficient enzyme activity in plasma but not Fabry disease. Thus, clinical symptoms that prompted Fabry disease investigation could not be attributable to Fabry disease and therefore enzyme replacement therapy was not indicated.

Is the alpha‐galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review

“…Only light microscopic preparations were available, electron microscopy investigations were not reported. One male hemizygote with chronic kidney disease in dialysis and low AgalA activity had histopathologic findings suggestive of hypertensive nephrosclerosis with no histologic changes compatible with Fabry nephropathy 17 . The other kidney biopsy was performed in a 52‐year‐old hemizygote with chronic kidney disease with normal enzyme activity and no elevated lyso‐Gb 3 in plasma at presentation.…”

“… a AgalA cut off/reference values in blood: superscript formatted numbers indicate the relevant reference 10 Dried Blood Samples, subjects with abnormal AgalA had 56.2‐87.5% activity of the mean; 16 not mentioned; 17 >2.2 μmol/L/h; 18 3.4‐13.0 mol/L; 21 3.4‐14.3 nmol/h/ml; 22 >8 nmol mu/h/ml; 23 Dried Blood Samples 20‐65nmol/mg/h; 24 0.4‐1.0 nmol/min/mg protein; 25 not mentioned; 26 >2nmol/h/ml; 27 mean 9.4±3.2 nm/h/ml; 19 >3.1 μmol/l/h. …”

“…We identified 15 studies 5,10,[15][16][17][18][19][20][21][22][23][24][25][26][27] comprising a total of 85 individuals (23 males, 62 females, mean age 41.6 ± 18.6, median 44, age range 6-78 years old) who were genetically screened because they were suspected with FD or were family members of FD patients or family members of carriers of an FD related variant. One male with two variants in the GLA gene (the pathogenic variant p.Gly411Asp (c.1232G>A) and the p.Asp313Tyr) had enzyme activity <5%, elevated lysoGb 3 and presented with the classical FD phenotype, was excluded from the analysis.…”

“…One male hemizygote with chronic kidney disease in dialysis and low AgalA activity had histopathologic findings suggestive of hypertensive nephrosclerosis with no histologic changes compatible with Fabry nephropathy. 17 The other kidney biopsy was performed in a 52-year-old hemizygote with chronic kidney disease with normal enzyme activity and no elevated lyso-Gb 3 in plasma at presentation. Initially, the renal biopsy was interpreted as focal segmental glomerulosclerosis lesions.…”