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Page 12 of 29 Aguiar. Rare Dis Orphan Drugs J 2024;3:13 https://dx.doi.org/10.20517/rdodj.2023.56

patients with LV hypertrophy and in about 50% of the patients without LV hypertrophy (this subgroup had
lower global longitudinal strain by speckle tracking and higher LV filling pressure), with lower values in
male patients [83,84,136,151] . In pediatric age, the native T1 is within the normal range, but in the pre-
hypertrophic phase, it falls linearly with increasing age, and during adulthood, this decrease is less
pronounced, although still significant; in the phase of overt hypertrophy, this correlation reverses (native T1
increases with the indexed LV mass) in male patients (remaining below the lower limit of normal) and the
two variables become non-related in female patients . These data suggest that low T1 is a possible early
[83]
marker of cardiac involvement and 3/4 phases of myocardial involvement are identified: phase 1: no
involvement (early accumulating phase); phase 2: low T1 and early myocardial dysfunction (late
accumulating phase); phase 3: LV hypertrophy with low T1 (characterized by inflammation, myocyte
hypertrophy, and limited LGE); phase 4: “pseudonormalization” of T1, fibrosis, and heart failure (as
extensive fibrosis and scarring present high T1 values) [83,151] .

A significant inverse correlation between native T1 and high-sensitivity troponin or plasma lyso-Gb3 was
identified [84,157,158] . Only very limited data are published about the prognostic value of native T1; one study
reported that native T1 at baseline was significantly associated with disease progression (measured by
FASTEX scale) at 12 months, with 100% of the progressing patients presenting low native T1, in comparison
[159]
with only 53% of patients with no clinical progression .
The effect of DST on native T1 was assessed in few studies, showing a trend for an increase during
treatment with either ERT or migalastat, mainly in younger and less severely affected FD patients [87,88,147] .

T2 mapping
Only few studies evaluated T2 mapping, a biomarker of myocardial edema (related to inflammation), in FD,
but no difference between FD patients and healthy controls, as well as no correlation with LV mass or left
atrium volume, was found . However, T2 in LGE areas is significantly higher in comparison with patients
[159]
with HCM or ischemic heart disease, and T2 in basal inferolateral wall is associated with GLS impairment, is
the strongest predictor of troponin, and predicts clinical worsening after 1 year [85,86] .

Other imaging techniques
Other imaging techniques have been used to identify inflammation in FD cardiomyopathy. Hybrid
techniques, such as positron emission tomography (PET)-MRI, have been studied for this purpose. These
studies have revealed higher T1 native in the segments exhibiting higher F-fluorodeoxyglucose uptake, and
18
a higher coefficient of variation in the isotope uptake has been associated with worse global longitudinal
systolic strain measured by echocardiography [160,161] .

Cardiac scintigraphy is a useful tool to evaluate myocardial perfusion and energy metabolism. In FD, studies
[162]
showed that energy depletion was associated with cardiac events and that sympathetic neuronal damage
may precede myocardial damage, e.g., fibrosis [163,164] .

FABRY DISEASE NEPHROPATHY BIOMARKERS
Estimating glomerular filtration rate
Reproducible and accurate estimates of renal function are essential in the management of FD. There are
limitations in all current equations to estimate GFR, but Modification of Diet in Renal Disease (MDRD)
equation is not validated in patients with higher GFR (knowing that a hyperfiltration stage has been
[165]
described in FD nephropathy) and seems less accurate than Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI creatinine2009 ) equation . Thus, CKD-EPI creatinine2009 equation is the recommended
[166]