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Page 4 of 29 Aguiar. Rare Dis Orphan Drugs J 2024;3:13 https://dx.doi.org/10.20517/rdodj.2023.56

Table 1. Systemic disease biomarkers used in clinical practice
Clinical
Biomarker Diagnosis Phenotype ERT monitoring References
correlations
Gb3 Not useful Not useful Poor: Decrease during ERT: [27,28,30,33,
(plasma/urine) • Plasma Gb3 with • Correlation with 36]
cerebral clinical endpoints not
complications (♂) established
• Urinary Gb3 with
eGFR, PCR, and ACR
Lyso-Gb3 Added value (cautious Added value (excellent diagnostic • ♀: LV mass and Decrease during ERT: [40,41,43,46,
(plasma) interpretations of accuracy in discriminating between MSSI • ♀: correlation with 49,61]
results) phenotypes and genders) • ♂: WML decrease in LV mass
and HR to WML

ERT: Enzyme replacement therapy; Gb3: globotriaosylceramide; eGFR: estimated glomerular filtration rate; PCR: protein-to-creatinine ratio; ACR:
albumin-to-creatinine ratio; LV: left ventricle; MSSI: mainz severity score index; WML: white matter lesions; HR: hazard ratio.

to-creatinine ratio (ACR) [27,33] . Finally, there was significant decrease in plasma and/or urine Gb3 in patients
treated under the clinical trials of both ERT preparations [22,24,34,35] ; however, the correlation between this
decrease and the therapeutic outcome in terms of “intermediate” or “hard” endpoints is not
established [28,30,36] . Moreover, in one study, the occurrence of anti-ERT antibodies was accompanied by a
blunted decrease in urinary Gb3, but the clinical significance of this finding remains unclear . The
[37]
limitations of Gb3 in terms of predictive value for FD manifestations are not surprising, given that
prominent Gb3 has been noted in placental tissues of FD male patients [38,39] , with the onset of clinical
complications occurring only several years later; thus, as mentioned above, other factors in addition to Gb3
[1]
may participate in pathogenesis .

Globotriaosylceramide
Given the limitations of Gb3 as a biomarker, research on Gb3 metabolites identified a product of Gb3
deacetylation, globotriaosylsphingosine (lyso-Gb3), which is hydrophilic and highly diffusible and whose
plasma levels in FD patients are markedly increased (exceeding those of controls by more than one order of
magnitude and most prominent in male patients) [Table 1] [1,40] .

Role in diagnosis and phenotype evaluation
In male patients with classical phenotype, several studies showed very high values of plasma lyso-Gb3 [30,40-43] ;
however, even hemizygotes with late-onset phenotypes presented increased lyso-Gb3 levels (though in
lower magnitude than patients with classical phenotype) [1,31,44-52] .

Regarding female patients, the classically affected heterozygotes usually present with increased plasma lyso-
Gb3 levels (in a magnitude similar to late-onset male patients) [43,47] , contrary to female patients carrying
mutations associated with late-onset phenotypes (e.g., p.F113L, p.N215S or IVS4 + 919G>A), where plasma
lyso-Gb3 is often normal [31,44-46,48,50,51] . Despite this limitation of lyso-Gb3 in the diagnosis of female patients,
the sensitivity of plasma lyso-Gb3 is much higher, in comparison with α-galactosidase A activity, to identify
female patients with FD [43,53] . Additionally, this sensitivity may be further increased using the α-galactosidase
A activity to plasma lyso-Gb3 ratio .
[54]

Moreover, plasma lyso-Gb3 presented excellent diagnostic accuracy in discriminating between classical and
late-onset phenotypes in male and female patients [Figure 1], with an area under the curve of 0.990 and
0.954, respectively [46,49] .