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Page 395 Chandramohan et al. J Transl Genet Genom 2024;8:394-404 https://dx.doi.org/10.20517/jtgg.2024.38

Conclusion: Females with Fabry disease, despite having normal reference range creatinine, minimal proteinuria,
and low plasma Lyso GL-3, had significant histologic evidence of the disease. When possible, histologic assessment
should be performed in females to assess tissue involvement. Longitudinal follow-up is needed to determine if
histologic findings on presentation predict long-term outcomes.

Keywords: Fabry disease, alpha-galactosidase A, glycosphingolipidosis, kidney biopsy, podocytes, proteinuria.

INTRODUCTION
Fabry disease (FD) is the most prevalent lysosomal storage disorder. It is an X-linked inborn error of the
glycosphingolipid metabolic pathway due to the deficiency of α-galactosidase A (GLA) that results in
lysosomal accumulation of globotriaosylceramide (GL-3) and its derivative globotriaosylsphingosine (Lyso
GL-3) in various cells, leading to clinical manifestations. Females with FD are heterozygous for the Fabry
gene mutation .
[1,2]
Historically, females were considered asymptomatic “carriers” of the defective GLA gene and invulnerable
to the clinical manifestations of FD. However, it is now known that heterozygous females have a variable
[3-6]
course that ranges from asymptomatic disease to a severe phenotype resembling that in males . These
observed differences in the phenotypic variation may be due to skewed X-chromosome random
inactivation, resulting in a higher percentage of cells with active X chromosomes expressing the mutation.
Consequently, the affected cells have less or no GLA-enzyme activity, affecting vital organ functions
(kidney, heart, and brain) .
[7]

When renal involvement occurs, glycosphingolipids accumulate in the glomeruli, particularly the
podocytes, leading to proteinuria. If not detected and treated early, this can cause a progressive decline in
kidney function . Female manifestations of kidney disease often go under-recognized for multiple reasons.
[8]
The serum creatinine measurement often underestimates renal dysfunction in women due to reduced
[9]
muscle mass . For any given estimated glomerular filtration rate (eGFR) value, creatinine levels are usually
lower in females versus male counterparts despite having similar normal creatinine reference ranges.
Females can have a significant decline in eGFR despite having creatinine values in the normal reference
range. In addition, during the collection of the data, most hospitals reported the eGFR using the
Modification of Diet in Renal Disease (MDRD) equation, a formula whose accuracy declines at higher GFR
2
[10]
levels; thus, only values less than an eGFR of 60 mL/min/1.73m are reported . Biomarkers, specifically
GL-3 and Lyso GL-3, are detected in the plasma and urine of patients with FD. However, GL-3 and
Lyso GL-3 are also considered less reliable in females and could be inadequate for assessing response to
enzyme replacement therapy [11,12] .

Kidney biopsies have proven reliable in diagnosing and evaluating FD's histologic involvement. However,
due to their invasive nature, biopsies are not typically the first choice as a diagnostic tool and are usually
reserved for patients with elevated creatinine or those with more than 500 mg of proteinuria per day . As
[13]
many as 40% of heterozygous females have kidney dysfunction, but there is a paucity of data on the early
pathological changes and kidney biopsy findings in females .
[14]

Renal biopsies were performed based on clinical suspicion of Fabry nephropathy, even in the absence of
proteinuria. We have analyzed and summarized the kidney biopsy findings in female patients with FD
whose creatinine at the time of biopsy was in the normal range and who had minimal proteinuria of < 500
mg/day by urine protein-creatinine ratio (UPCR).