Biomarkers in anderson-Fabry disease: what should we use in the clinical practice?
Abstract
Major organ involvement in Anderson-Fabry disease (FD) is clinically silent for a long period and clinically heterogeneous; thus, it is difficult to identify the patients at increasing risk of a progressive disorder. Moreover, accumulating evidence suggests that early disease-specific treatment (DST) is safe and effective in preventing the progression of heart and kidney damage, with poorer results in patients with extensive myocardial fibrosis, advanced glomerulosclerosis, and/or heavy proteinuria. Therefore, biomarkers defining preclinical involvement, with a prognostic value and a correlation with response to treatment, are an urgent need in FD. Several types of biomarkers are recognized in FD, pertaining to total disease burden and specific organ involvement (central nervous system, heart, and kidney). Currently, plasma globotriaosylsphingosine (lyso-Gb3), cardiac and brain imaging, and albuminuria are recognized as the “gold standard” biomarkers of total disease burden or specific organ involvement in FD. However, severe globotriaosylceramide (Gb3) storage and organ damage may occur within the affected organs with minimal changes in these standard tests. Given the heterogeneity and rarity of the disease, the identification of new biomarkers is challenging. Several ways may be used to identify new biomarkers in FD, namely “omic” medicine, biomarkers identified in other pathological models similar to FD, and biomarkers linked to the pathophysiological pathways involved in FD. This article aims to review the clinical value of the available biomarkers in FD and give an overview of the research on new biomarkers.
Keywords
INTRODUCTION
Biological markers or biomarkers are defined, according to the National Institutes of Health Biomarkers Definitions Working Group, as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”[1]. Biomarkers may have great value in several clinical applications, including their use as diagnostic tools, for staging or classifying the extent of the disease, disease progression and prognosis, predicting and monitoring clinical response to an intervention, and facilitating early evaluation of efficacy and safety in clinical trials[1]. However, rigorous validation of the relationship between a proposed biomarker, disease activity, and outcome is of key importance[2].
Candidate biomarkers for lysosomal storage disorders (LSDs) are mainly analytes and imaging techniques. Analytes may range from simple metabolites to complex proteins and, for LSDs, can be divided into two categories: molecules that accumulate in tissues and body fluids directly due to the enzymatic defect, and molecules produced by the cells in response to lysosomal storage[3].
One of the most urgent needs in Anderson-Fabry disease (FD) is for reliable and validated biomarkers, ideally measured by non-invasive testing. This urgency is mainly related to the characteristics of and pitfalls in FD: diagnosis, determination of phenotype (classical vs. late-onset), evaluation of preclinical involvement, monitoring and assessment of treatment response.
The diagnosis of FD is based mainly on the enzymatic activity of α-galactosidase A and GLA gene sequencing, but both methods have limitations that need to be addressed. Due to random X chromosome inactivation, female patients may present significant residual enzymatic activity and about one-third may have α-galactosidase A activity within the normal range for the general population; thus, the diagnosis can only be reliably performed by GLA sequencing[4]. Moreover, in male patients with residual enzymatic activity (> 5% of normal)[5,6] definitive diagnosis of FD may only be confirmed by GLA gene mutation analysis[7]. However, GLA gene sequencing may not provide a definitive diagnosis for several reasons: most GLA mutations found in FD patients are novel/“private”, there are various mutations of unknown significance, and routine sequencing can only identify a mutation in 97% of male patients with FD[7,8]. Hence, reliable biomarkers may help diagnosis in these situations[1].
Furthermore, FD is clinically heterogeneous (in presentation and rate of progression)[9-12], with genetic factors and gender certainly contributing to this fact[13,14]. However, the clinical picture may vary widely even in patients within the same family or with the same mutation, and thus other genetic, epigenetic, and environmental factors also contribute to clinical heterogeneity. Therefore, the identification of prognosis biomarkers and biomarkers capable of determining the likely phenotype (classical vs. late-onset) is paramount to the identification of patients at increased risk of a progressive disorder[1].
FD is clinically silent for a long period; per example, severe storage material inclusions in podocytes and distal tubules, as well as segmental foot process effacement and nonspecific degenerative lesions, have been identified even at early stages of Fabry nephropathy, in pediatric and adult patients with minimal or no alterations in standard renal tests (namely glomerular filtration rate, albuminuria or proteinuria)[15-20]. Although the optimal timing of disease-specific treatment (DST) beginning is not known, increasing evidence suggests that an early treatment strategy may be more effective in preventing cardiac and renal manifestations and major clinical events. However, currently, the European recommendations for DST initiation are based on functional or structural manifestations[21]. Nonetheless, as mentioned above, there is a long clinically silent period before overt major organ manifestations, characterized by histological changes (often irreversible lesions) or transcriptional profiles, whose detection depends on invasive procedures. Consequently, the identification of non-invasive biomarkers of preclinical involvement of the organs may have a profound impact on the treatment decisions, whether these biomarkers prove to have prognostic value[1].
Finally, FD is a relatively slowly progressive disorder, with major events occurring mainly in adulthood. This fact constitutes a major difficulty in the design of clinical trials[22-24], because long follow-up periods are required to demonstrate the benefits of any therapeutic intervention. Therefore, the identification of surrogate biomarkers of response to treatment, with rigorous correlations with clinical outcomes, is essential in the evaluation of the therapeutic strategies that are available or under development[1].
FABRY DISEASE BIOMARKERS USED IN THE CLINICAL PRACTICE
Currently, there are no proper or well established/validated plasma or urinary biomarkers for FD. However, there are several biomarkers (imaging techniques and analytes [metabolites related to lipid abnormalities or proteins]) that are used in clinical practice with some limitations. These biomarkers may reflect the systemic disease burden or manifestations in a particular organ.
SYSTEMIC DISEASE BURDEN BIOMARKERS
Metabolites related to lipid abnormalities have been used as the main biomarkers of FD systemic burden, namely globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3).
Research of potential protein biomarkers for FD showed a lack of prominent plasma protein abnormalities. However, several biomarkers mainly related to inflammation and endothelial dysfunction have been studied, but not widely validated and, consequently, are not currently used in clinical practice[1].
Globotriaosylceramide
FD is characterized by a disruption in glycosphingolipids metabolism, so lipid abnormalities have been studied as potential biomarkers. For a long time, the primary accumulating substrate Gb3 has been considered a surrogate marker for FD [Table 1], and its reduction in the endothelium has served as an indicator for the development and registration of enzyme replacement therapy (ERT) with agalsidase β[1,22,25].
Systemic disease biomarkers used in clinical practice
| Biomarker | Diagnosis | Phenotype | Clinical correlations | ERT monitoring | References |
| Gb3 (plasma/urine) | Not useful | Not useful | Poor: • Plasma Gb3 with cerebral complications (♂) • Urinary Gb3 with eGFR, PCR, and ACR | Decrease during ERT: • Correlation with clinical endpoints not established | [27,28,30,33,36] |
| Lyso-Gb3 (plasma) | Added value (cautious interpretations of results) | Added value (excellent diagnostic accuracy in discriminating between phenotypes and genders) | • ♀: LV mass and MSSI • ♂: WML | Decrease during ERT: • ♀: correlation with decrease in LV mass and HR to WML | [40,41,43,46,49,61] |
Role in diagnosis and phenotype evaluation
Gb3 is not only found inside the cells, but it has been recognized for a long time that its concentration is increased in plasma and urine in FD male patients[26]. Plasma and urine Gb3 values are more strikingly elevated in FD males and plasma Gb3 is elevated in only a small percentage of female patients (15%-30%), and urinary Gb3 may be within the normal range in 8%-13% and 12%-20% of male and female patients, respectively[27,28]. There is a correlation between types of mutations and urinary Gb3 excretion, with patients with missense mutations, mainly those associated with late-onset phenotypes, presenting lower values, most of which within the normal range, even in male patients[29-31]. Thus, the added value of Gb3 for diagnostic purposes is at least questionable[1].
Role in clinical monitoring and assessment of treatment response
The correlation between plasma or urinary Gb3 and clinical manifestations and its added value to monitor progression of FD is also poor, without correlation with age, most of clinical parameters, and total disease severity (measured by Mainz Severity Score Index [MSSI])[32]; however, plasma Gb3 is significantly higher in male patients with cerebral complications (compared with those without) and urinary Gb3 significantly correlates with estimated glomerular filtration rate (GFR), urine protein-to-creatinine ratio, and albumin-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[37]. The 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 may participate in pathogenesis[1].
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].
Figure 1. Plasma lyso-Gb3: sub-analysis by gender in male and female patients with Fabry disease[46]. Lyso-Gb3: Globotriaosylsphingosine.
However, the discriminative power of plasma lyso-Gb3 in male and female patients with variants of unknown significance, like p. R118C, p.R112H, and p.P60L, seems limited, as lyso-Gb3 is not increased in this group of patients (even in patients with histological demonstration of Gb3 storage in podocytes)[31,41,45,55,56]. Nonetheless, recently, nano-liquid chromatography-tandem mass spectrometry (a technique enabling the detection of extremely low concentrations of lyso-Gb3, with greater sensitivity than conventional techniques), in patients with variants of unknown significance (p.R112H and p.M296I), demonstrated that lyso-Gb3 was lower than in classical and late-onset phenotypes FD patients having other variants, but higher than in those with functional variants (p.E66Q) and healthy subjects[1,57].
The performance of urinary lyso-Gb3 as a diagnostic tool seems similar to that of plasma lyso-Gb3, with only a minority of patients excreting undetectable amounts and with patients presenting missense mutations or mutations associated with late-onset phenotypes having significantly lower excretion of lyso-Gb3[33,47]. Thus, lyso-Gb3 seems to be a promising diagnostic biomarker, with added value for diagnosis in specific situations, but evaluation of pathogenicity of mutations based solely on this parameter should be cautious[1].
Role in clinical monitoring
Various correlations have been found between plasma lyso-Gb3 and clinical manifestations. However, as stated previously, given the large differences in plasma lyso-Gb3 levels between male and female genders or classical and late-onset phenotypes, a sub-analysis by these subgroups is paramount in order to avoid the confounding factor of disease severity (higher in males and classical phenotype) and to understand the true clinical correlations and prognostic value of plasma lyso-Gb3 in single patients, for whom the gender and phenotype are already known; thus, in a study with analysis by these sub-subgroups, only significant clinical correlations were found between plasma lyso-Gb3 in classical males and indexed LV mass, as well as between plasma lyso-Gb3 in classical females and total MSSI [Table 2][46].
Correlation between lyso-Gb3 and clinical variables in male and female patients (sub-analysis by phenotype)[46]
| All patients (n = 73) | Males | Females | |||
| Classical (n = 18) | Late-onset (n = 11) | Classical (n = 29) | Late-onset (n = 15) | ||
| Age | 0.001 | 0.325 | -0.247 | 0.309 | 0.082 |
| Age at ERT initiation (n = 50) | -0.466* | 0.088 | -0.071 | 0.230 | -0.100 |
| MSSI | 0.538* | 0.458 | -0.251 | 0.441* | 0.404 |
| FIPI | 0.383* | 0.424 | -0.196 | 0.259 | 0.363 |
| Indexed LV mass | 0.353* | 0.776* | -0.327 | 0.303 | 0.045 |
| NT-pro BNP (n = 24) | 0.247 | - | - | - | - |
| Albuminuria | 0.317* | 0.079 | -0.600 | 0.133 | 0.380 |
| eGFR | -0.168 | -0.066 | 0.345 | -0.125 | 0.015 |
In male patients with classical phenotype, lyso-Gb3 does not increase with age[49] (with markedly increased values even in neonates, which increases rapidly during the first months of life)[58] and consequently does not correlate strictly with disease severity indexes or clinical manifestations, except for a significant correlation with the presence of white matter lesions[1,40,41]. One study described a significant correlation between plasma lyso-Gb3 and MSSI in male patients, but there was no discrimination between patients with classical and late-onset phenotypes[43].
Contrariwise, in late-onset phenotype male patients (presenting p.N215S variant), there was a significant increase in plasma lyso-Gb3 with age and it presented significant correlations with left ventricular (LV) mass and GFR[48]; these results were in contrast with the ones of other studies, showing no correlations between plasma lyso-Gb3 and age, clinical manifestations or disease severity indexes in male patients with late-onset phenotypes [Table 2][46].
In females, lyso-Gb3 tends to increase progressively with age[49] and significant correlations have been found between lyso-Gb3 and MSSI, LV mass, and carotid intima-media thickness[40,41,59]. Contrariwise, another study found no correlation between plasma lyso-Gb3 and MSSI in females[43].
There are no well-established correlations between plasma lyso-Gb3 and kidney function parameters, but a significant correlation between urinary lyso-Gb3 and urine protein-to-creatinine ratio or ACR has been observed; however, this correlation was observed in a cohort of male and female patients and no adjustment for gender was reported[1,33]. Another study also reported a significant correlation between plasma lyso-Gb3 and serum creatinine, protein-to-creatinine ratio or indexed LV mass in multivariate analysis adjusted for gender and phenotype[49].
As lyso-Gb3 seems to be a risk factor directly implied in FD pathogenesis, lifetime exposure to plasma lyso-Gb3 (estimated product of lyso-Gb3 concentration by age) should correlate better with disease (mainly in male patients, showing very high values from birth) than the current lyso-Gb3 level. Therefore, both in male and female patients, plasma lyso-Gb3 exposure is significantly correlated with disease severity, clinical manifestations, and the cold detection threshold and thermal sensory limen of the upper limb (both signs of characteristic FD small fiber neuropathy)[1,41,48,60]. However, as FD is a storage disorder with a progressive accumulation of substrates along patients’ life, older patients tend to have more severe manifestations; thus, the analysis of plasma lyso-Gb3 over a lifetime is biased by the age effect on disease severity.
Therefore, the correlations between plasma lyso-Gb3 and clinical variables are limited, with contradictory results among studies and most of the studies not reporting a sub-analysis by gender and phenotype, biasing the results and precluding comparisons between them. Moreover, no proper longitudinal studies with repeated measurements of plasma lyso-Gb3 are available within the literature in order to evaluate its prognostic value, and even patients with plasma lyso-Gb3 within the normal range may present clinical events[51].
Role in the assessment of treatment response
Lyso-Gb3 decreases significantly with any of the three available ERTs (with a more pronounced decrease in classically affected males), but does not reach normal values, even in female patients, independently of ERT preparation[30,40,42,52,61-63]. Moreover, in classically affected males developing anti-ERT antibodies, reduction of plasma lyso-Gb3 is relatively poor[40,42,52,61,64], mainly in patients treated with agalsidase α (with a significant difference between patients with and without anti-drug antibodies)[60]. One study reported that classically affected males starting treatment before 25 years of age have a greater decrease in plasma lyso-Gb3 compared with patients starting ERT later in life, with this difference remaining significant even after adjustment for plasma lyso-Gb3 at baseline, ERT preparation, and ERT dose. Furthermore, the patients starting ERT at an earlier age presented a trend for less formation of anti-ERT antibodies, and there were fewer clinical events in the group of patients treated earlier, but the clinical meaning of the former finding is unclear due to an age bias[65].
In patients treated with the chaperone migalastat, there is also a significant decrease in plasma lyso-Gb3 in the first six months of therapy in treatment-naïve patients[66,67]. Moreover, in patients previously treated with ERT, plasma lyso-Gb3 remained stable after switching from ERT to migalastat[67-70]. In patients treated with migalastat but non-amenable in vivo, there is no decrease or increase in plasma lyso-Gb3 in treatment-naïve patients or patients switching from ERT, respectively[66,68,71,72]. However, in a single study, no significant correlation was found between plasma lyso-Gb3 change during treatment and the increase in leucocyte activity after migalastat initiation[71].
The reduction in plasma lyso-Gb3 during ERT was found to correlate with the correction of LV mass in female patients and with a lower hazard ratio for developing new cerebral white matter lesions in male and female patients[61]. However, in another longitudinal study, with a subanalysis by gender and phenotype and comprising mainly late-onset phenotype patients, there was no correlation between the change of plasma lyso-Gb3 and the change of LV mass in both classical and late-onset FD patients[73]. This absence of correlation between plasma lyso-Gb3 and treatment outcomes was further confirmed in a large cohort of FD patients, showing that plasma lyso-Gb3 before treatment initiation, plasma lyso-Gb3 absolute decrease, or plasma lyso-Gb3 relative decrease did not predict the risk of event during ERT[74]. The same results, with no correlation between changes in lyso-Gb3 and LV mass, GFR, or clinical events, were found for patients treated with migalastat[75]. These results are in conflict with a single study showing a correlation between baseline lyso-Gb3 and the risk of an event during a median follow-up of 68 months, but all but one event occurred in classical phenotype patients, and when baseline lyso-Gb3 was added to a multivariable logistic regression model containing age, sex, phenotype and ERT as other covariates to identify the risk of an event, no significant improvement was found[76]. Thus, the value of plasma lyso-Gb3 to monitor response to DST seems at least questionable, and its correlation with clinical outcomes clearly needs further investigation in larger cohorts of FD patients.
FABRY DISEASE CARDIOMYOPATHY BIOMARKERS
Currently, imaging techniques are the most commonly used biomarkers of cardiac injury in FD, but some biochemical biomarkers are also used in clinical practice [Table 3].
Fabry disease cardiomyopathy biomarkers used in clinical practice
| Biomarker | Preclinical evaluation | Clinical correlations | ERT monitoring | References |
| Cardiac troponin | Not useful | • LV wall thickness • LGE volume in cardiac MRI • T2 in basal inferolateral wall | Remained stable during DST | [79,80,86-88] |
| NT-proBNP | Not evaluated | • Diastolic dysfunction parameters and LV mass • T2 in basal inferolateral wall • Inverse correlation with T1 | Remained stable during DST | [83,86-88,91-93] |
| Echocardiogram (TDI) | Superior to conventional echocardiography in the detection of early cardiac involvement | LV wall thickness | ERT successfully prevented the appearance of abnormal TDI velocities | [99-101] |
| Echocardiogram (speckle-tracking) | Better sensitivity than TDI in detecting early diastolic dysfunction | • LGE in cardiac MRI • Functional status • Risk of cardiovascular events • Risk of WML | ERT improves: • Systolic strain and strain rate (?) • LA peak positive strain | [93,105,106,108,109,118-120,122,123] |
| Cardiac MRI (LGE) | LGE amount correlates with: • LV mass • Regional myocardial function • Risk of ventricular arrhythmias | Not useful: • LGE amount increase during ERT • Major predictor of response to ERT | [82,93,121,124,143] | |
| Cardiac MRI (T1 mapping) | Characteristic decrease in native T1 | Staging of FD cardiomyopathy in | Improvement during DST, mainly in earlier stages | [83,85,87,88,146,150] |
Troponin
Role in clinical monitoring
Cardiac troponins are well-validated biomarkers of cardiomyocyte injury. New generation/high-sensitivity assays for cardiac troponin T enable the identification of minimal cardiac injury and have been associated with poor outcomes in cardiomyopathies other than ischemic heart disease[77,78]. Two studies evaluating the performance of troponin I as a biomarker of FD cardiomyopathy have shown that this analyte was elevated in 21%-37% of the patients, with a very high diagnostic accuracy for LV hypertrophy or late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging (MRI)[79,80]. Comparable results were obtained with high-sensitivity troponin T[81-85] and one study showed a strong correlation with T2 in basal inferolateral wall[86]; in a retrospective analysis, over a follow-up period of 3.9 years, patients with elevated troponin at baseline had significantly increasing replacement fibrosis[81].
Role in the assessment of treatment response
High-sensitivity troponin T remained stable in the first 12 months after ERT initiation, while increased in untreated patients or in treated patients with advanced cardiomyopathy[87]. This biomarker also remained stable within the first 18 months after migalastat initiation[88].
Brain natriuretic peptide
Role in clinical monitoring and assessment of treatment response
Brain natriuretic peptide and the N-terminal fragment of its prohormone (NT-proBNP) have an established role in determining the diagnosis and prognosis of heart failure[89,90]. NT-proBNP was evaluated as a biomarker of early cardiac involvement in FD, showing significant correlations with parameters of diastolic dysfunction and LV wall thickness[91,92]. Other studies showed that NT-proBNP is significantly higher in patients with LGE in cardiac MRI and presented a significant correlation with the amount of LGE and the T2 in the basal inferolateral wall and an inverse correlation with native T1[83,86,93]. NT-proBNP remained stable after ERT or migalastat initiation[87,88].
Echocardiography
Nonetheless, cardiac imaging techniques are the mainstay in the assessment of FD cardiomyopathy. Conventional two-dimensional and Doppler echocardiography is the standard imaging tool in the identification and staging of cardiac involvement in FD disease, but it is not suitable for detecting subtle myocardial dysfunction in the early course of FD cardiomyopathy[94,95]. Therefore, advanced echocardiography techniques, such as tissue Doppler imaging (TDI) and strain and strain rate (SR) speckle-tracking based echocardiography have been used in early cardiac involvement that precedes overt LV hypertrophy and appearance of replacement myocardial fibrosis. Recently, an echocardiographic-based staging of FD cardiomyopathy was proposed and was demonstrated to have clear prognostic value. FD cardiomyopathy was categorized into four stages: stage 0 (no cardiac involvement); stage 1 (LV hypertrophy); stage 2 (left atrium enlargement); stage 3 (ventricular impairment, defined as LV ejection fraction < 50% or E/e′ ≥ 15 or TAPSE < 17 mm)[96].
Tissue Doppler imaging
There are several studies establishing the added value of TDI in the early detection of FD cardiomyopathy[97-103]. In the first study on the evaluation of TDI in FD cardiomyopathy, it was reported that echocardiography did not show any difference between FD patients without LV hypertrophy and controls in conventional parameters of diastolic dysfunction, but there was a significant decrease in myocardial systolic and diastolic velocities, even in FD patients without LV hypertrophy (although of lesser magnitude than in patients with overt LV hypertrophy)[100]. These results were further confirmed in several cohorts of patients[87,88,97-99,101,103]. Abnormalities of systolic velocities in the right ventricle (RV), measured by TDI, have been recently described[104].
Furthermore, it was identified a significant inverse correlation between systolic mitral annular velocity (S′) or early diastolic mitral annular velocity (E′) and interventricular septum (IVS) or left ventricle posterior wall (LVPW) thickness[101]. The diagnostic accuracy of TDI variables in detecting myocardial fibrosis was also evaluated, with both septal and lateral E/E′ ratios, an estimate of left ventricular end-diastolic pressure, presenting high diagnostic accuracy in predicting the presence of LGE in cardiac MRI[93].
Regarding treatment effect, agalsidase α successfully prevented the appearance of abnormal TDI velocities in the group of patients with normal echocardiograms at baseline)[102]. It was concluded that reduction in myocardial contraction and relaxation velocities in TDI are detectable before the development of LV hypertrophy or even abnormalities in the traditional parameters of diastolic function, thus enabling the recognition of preclinical cardiac damage.
Strain and strain rate speckle-tracking
New tools like strain and SR speckle-tracking based echocardiography (a TDI-derived technique) enable measurement of myocardial systolic and diastolic strains, which seem superior and more sensitive than myocardial velocities (measured by TDI) in quantifying changes of myocardial systolic function, because they are less influenced by overall cardiac motion[105].
Decreased systolic strain and SR of the LV have been reported in FD patients, compared with healthy controls[106-109]. These alterations in myocardial systolic strains are detectable even in the early stages of FD cardiomyopathy: there is a significant reduction in both global systolic longitudinal and circumferential strains, as well as an absence of the normal regional base-to-apex circumferential strain gradient, even in the subgroup of patients without LV hypertrophy[107,108,110-112]. Global longitudinal strain, mainly basal longitudinal strain, also correlated with LV mass, T1 mapping, or even the risk of “de novo” atrial fibrillation, major cardiovascular events, or stroke[110,111,113]. RV strain is also impaired in FD patients, but only in the hypertrophic stage[114] and may be lower than in patients with HCM[115].
Decreased LV diastolic strain and SR were also reported in FD[106,109], even in the early phases of FD cardiomyopathy (patients without LV hypertrophy) and with a higher sensitivity for detecting diastolic dysfunction compared to using TDI for early diastolic velocities[109]. Left atrial (LA) systolic and diastolic strain and SR are also decreased in FD patients, with a significant decrease in systolic SR even in patients without LV hypertrophy[116-118]; LA strain parameters are associated with atrial fibrillation and stroke[119] and peak atrial longitudinal strain also showed an inverse correlation with white matter lesions (WML)[120,121].
Speckle-tracking based echocardiography may also be a non-invasive tool for the detection of myocardial fibrosis in FD[122,123]. Global longitudinal systolic strain is lower in patients with LGE in cardiac MRI, with a significant correlation between global longitudinal systolic strain and the amount of LGE; furthermore, segmental strain values are particularly decreased in the LGE positive basal posterior and lateral segments[93,110,123]. Moreover, LV, RV, and LA strains are inversely linked to the heart failure functional class[106].
The effect of ERT in myocardial systolic and diastolic strains is still controversial: in a study with agalsidase β, there was a significant increase in both longitudinal and radial peak systolic SR and systolic strain after 12 months of treatment[124]; while in another study, in patients treated with ERT for a mean period of 3.1 years, there was no change in global systolic longitudinal or circumferential strain[107]. The improvement in systolic SR may be influenced by the presence and amount of myocardial fibrosis at ERT initiation, with a study showing a significant increase in radial systolic SR occurring only in the subgroup of patients without fibrosis; systolic SR remained essentially unchanged in patients with mild fibrosis, but rather decreased in the severe fibrosis subgroup[125]. ERT also seems to improve LA function by an increase in LA peak positive strain[119].
Magnetic resonance imaging
Cardiac MRI plays a critical role in the differential diagnosis of cardiomyopathies and is the diagnostic standard for assessing global and segmental cardiac morphology and function, with high spatial resolution and low observer variability, in patients with FD[126]. In patients under ERT, cardiac MRI can reliably evaluate its effects on LV mass in FD patients[23,122,124,127-130].
Late gadolinium enhancement
LGE imaging techniques using cardiac MRI are the gold standard for non-invasive detection of focal replacement fibrosis in the myocardium[131].
Between 31% and 77% of patients with FD disease may present LGE, with a characteristic mid-myocardial distribution (sparing the subendocardium) in the inferolateral basal and mid basal segments of the LV wall, that seems to be specific to FD cardiomyopathy[82,83,93,122,125,131-136]. Additionally, in FD, LGE was correlated with histologic findings (myocardial collagen deposition) from autopsy[137]. A greater proportion of male patients present larger amounts of LGE in cardiac MRI[83,131,133]; it was reported previously that only female patients might present LGE with normal LV mass[138], but recent reports showed that this is also true for some male patients[82,83,133,139].
Several studies have reported a significant correlation between the amount of LGE and LV mass[93,122,131,133,140,141], and LGE correlates with abnormalities in regional myocardial function assessed by speckle-tracking imaging studies[93,122,123,135,138,142]. However, the sensitivity of LGE to detect early cardiac involvement, as expected due to the identification of irreversible replacement fibrosis, is limited: LGE is uncommon in patients showing only TDI abnormalities (without LV hypertrophy)[93,143].
Cardiac fibrosis, evaluated by LGE in cardiac MRI, tends to increase progressively, mainly in patients with larger LGE volumes at baseline, even in patients with stable LV mass[82]. Moreover, the annual increase in LGE during the follow-up is an independent predictor of malignant ventricular arrhythmias, with sudden cardiac deaths only occurring in the group of patients with LGE[144]. Other studies confirmed that the presence and the extent of LGE, as well as maximal wall thickness, are associated with a greater risk of adverse cardiac events in FD patients[145,146].
ERT does not seem to have any effect on LGE: the amount of LGE significantly increased in patients treated for 12 months with agalsidase β (no patients without LGE at baseline developed LGE during ERT), and LV mass only significantly decreased in patients without LGE at baseline[122]. These results were further confirmed with longer treatment periods, also showing some patients developing LGE even during treatment with ERT[144]. Moreover, as previously mentioned, the presence of LGE is one of the most important predictors of response to ERT in terms of myocardial function and exercise capacity[125]. Similar results were found with migalastat, with no patients without LGE at baseline developing LGE during treatment, but with an increase in LGE in patients who initially present LGE[147].
T1 mapping
A novel technique, T1 mapping, enables the measurement of native myocardial T1 (non-contrast myocardial T1) and T1 after administration of gadolinium contrast. Native T1 allows for a better characterization of the myocardium content, with increased values in the setting of fibrosis, edema, or amyloid deposits and decreased values in iron overload or lipid storage. Measurement of T1 with extracellular gadolinium-based contrast agents gives additional information about the extracellular volume fraction and has been studied for assessment of diffuse fibrosis, with good histological correlations[148]. However, in FD, it has been more extensively studied as an imaging biomarker for early detection of cardiac involvement and for distinguishing FD from other etiologies of concentric remodeling and hypertrophy (due to lipid storage, yielding low native T1)[149], rather than for evaluation of diffuse fibrosis[150-154].
Very high (> 95%) diagnostic accuracy of native T1 in distinguishing between FD cardiomyopathy and other forms of cardiomyopathy has been reported[85,152,153,155,156]. Septal native T1 is low in around 90% of the 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[83]. These data suggest that low T1 is a possible early 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 with only 53% of patients with no clinical progression[159].
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[159]. However, T2 in LGE areas is significantly higher in comparison with patients 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 18F-fluorodeoxyglucose uptake, and 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 showed that energy depletion was associated with cardiac events[162] 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[165] is not validated in patients with higher GFR (knowing that a hyperfiltration stage has been described in FD nephropathy) and seems less accurate than Chronic Kidney Disease Epidemiology Collaboration (CKD-EPIcreatinine2009) equation[166]. Thus, CKD-EPIcreatinine2009 equation is the recommended equation to estimate GFR in adults with FD[167,168]. However, given that measured GFR by iohexol plasma clearance and isotopic methods is more accurate, depending on local availability, the precise measurement of the GFR is recommended for FD patients if the estimated GFR is > 60 mL/min/1.73 m2[168].
Cystatin C was proposed as a reliable marker of renal function [Table 4][169]. Cystatin C has been compared with creatinine in the evaluation of renal function in a cohort of patients treated with agalsidase α for 4 years, with no significant change in creatinine or in creatinine-based estimated GFR, but with a significant increase (just after only one year of ERT) in cystatin C and a concurrent decrease in estimated GFR by Hoek equation[170] (using cystatin C values). The authors concluded that cystatin C was an early marker for the decline of GFR, but no gold standard precise measurement of GFR was used to support this conclusion[171]. This finding was further corroborated by another study[92].
Fabry disease renal biomarkers used in clinical practice
| Biomarker | Diagnosis | Clinical correlations | ERT monitoring | References |
| Cystatin C | Better diagnostic accuracy than creatinine in detecting early renal involvement | Better correlation of cystatin C and creatinine-based equations with measured GFR (?) | More sensitive than creatinine in detecting a minor decline in GFR during ERT (?) | [92,169,171,172] |
| Proteinuria albuminuria | Earlier biomarker of FD nephropathy (limitations) | Good correlation with GFR decline (there are several patients with CKD stage ≥ 3 without overt proteinuria) | Does not respond to ERT | [15-20,177-184] |
Cystatin C-based estimation of GFR was compared with measured GFR in a relatively small validation study (including several cystatin and creatinine-based equations). In contrast to that previously mentioned, Hoek equation was less accurate than CKD-EPIcreatinine2009 equation in detecting GFR decline during ERT, but Stevens’ equation[172] (a creatinine and cystatin C-based formula) was the one that most closely approximated the measured GFR[173]. However, Stevens’ equation development was based on serum cystatin C assays in adults that were not traceable to standard reference material. Consequently, it is no longer recommended by international chronic kidney disease (CKD) guidelines[167].
Albuminuria/proteinuria
Role in the identification of preclinical involvement
Total urinary protein and albumin excretion can be considered important biomarkers in FD nephropathy [Table 4]. Proteinuria (> 150 mg/day) and albuminuria A2 are usually the first signs of renal involvement[174-177]. The sensitivity of albuminuria seems superior to that of total urinary protein excretion in detecting early renal involvement in FD[178]. Thus, albuminuria remains the best existing marker to detect early renal involvement, but the relevance of albuminuria A2 as a biomarker is largely based on validation studies in the earlier stages of other nephropathy models. Moreover, in FD, nephropathy albuminuria may result not only from glomerular damage of the filtration barrier, but also from tubular involvement with decreased reabsorption of filtered albumin.
However, the usefulness of albuminuria and/or proteinuria in identifying incipient FD nephropathy is questionable. Although there is a significant correlation between urinary protein excretion rates and foot process width and fractional volume of Gb3 inclusions in the podocytes[16], FD nephropathy is clinically silent for a long period and significant histological changes (including nonspecific degenerative lesions) may occur without pathological albuminuria and/or proteinuria[15-20]. In incipient stages of FD nephropathy, tubular reabsorption of albumin may overcome its increased excretion, limiting the sensitivity of this biomarker.
Prognostic value and role in the evaluation of treatment response
Furthermore, proteinuria also seems to play an important role in FD nephropathy progression, even in patients treated with ERT, because it is an independent risk factor affecting the extent of renal decline and is one of the determinants of the success of ERT[12,178-185]. For both genders, the proportion of patients with overt proteinuria (> 300 mg/day) and its magnitude and the prevalence of nephrotic range proteinuria are higher with more advanced CKD stages[12,178]. Moreover, comparing the GFR decline stratified by baseline proteinuria, higher baseline proteinuria levels were associated with more rapid GFR decline, but the patients with higher baseline proteinuria were also older and with lower baseline GFR[12,179]. Notwithstanding this, in one study, a regression model for GFR slope retained proteinuria as the most important indicator of renal disease progression in adult FD patients[179]. Therefore, there seems to be an influence of proteinuria in nephropathy progression, although the magnitude of this influence is not well established, as several studies, with both male and female patients, found no relationship between the degree of proteinuria and the rate of GFR decline, and in one study, 11% of the male and 28% of the female patients with estimated GFR
Finally, ERT does not seem to reduce proteinuria (mainly in male patients), so this biomarker does not serve as a good indicator of response to ERT.
Histological lesions
It is well known that substrate storage occurs in all renal cells, leading to progressive nephropathy characterized by nonspecific degenerative lesions, namely mesangial widening, segmental and/or global glomerular sclerosis, tubular atrophy, and interstitial fibrosis[15,187-190]. These well-known histological findings in advanced FD nephropathy contrast with the limited knowledge about the histology of patients with incipient nephropathy. Thus, histological biomarkers have been used in clinical practice to assess the prognosis of each individual patient.
Role in the identification of preclinical involvement
Lipid deposition-related lesions are characteristic of FD nephropathy, appearing as vacuoles or inclusions, according to the applied technique. The characteristic severe inclusions in podocytes and distal tubules, as well as segmental foot process effacement, have been shown even at early stages of Fabry nephropathy in pediatric and adult patients with minimal or no alterations in standard renal tests[15-20]. Moreover, mesangial and endothelial cell inclusions, as well as nonspecific degenerative lesions, such as mesangial widening, glomerulosclerosis, tubulointerstitial fibrosis, and arteriopathy, have also been described in this group of patients[15,17,19]. These data confirm that clinically silent deposition of Gb3 begins in early childhood, long before overt FD nephropathy, with a wide variation in the individual progression of glomerulosclerosis and interstitial fibrosis and development of end-stage renal disease[12].
Prognostic value
The importance of these specific pathological findings as potential surrogate markers for the progression of renal dysfunction is uncertain and needs to be further studied longitudinally. In contrast to semi-quantitative scoring systems for intracellular Gb3 inclusions, using light microscopy, that has failed to show any correlation with age, proteinuria, and GFR[9,15,17,191], a small study with 14 FD patients, using quantitative stereological electron microscopy methods, has shown significant correlations between podocyte Gb3 fractional volume of inclusions by cytoplasm or foot process width and age or proteinuria[16]. Conversely, chronic nonspecific glomerular and tubulointerstitial lesions seen in kidney biopsies seem to correlate better with the natural history and manifestations of FD nephropathy (GFR and proteinuria)[9,15,191,192].
Role in the evaluation of treatment response
Histological biomarkers have also been used as surrogate endpoints to assess the response of FD to DST, showing a significant increase in the percentage of normal glomeruli in the agalsidase α phase III clinical trial[24]; a significant decrease in the inclusion score in the kidney microvascular capillary endothelial cells in the agalsidase β phase III clinical trial, with a complete clearance of the endothelial, mesangial and distal convoluted tubule/collecting duct cells after 54 months of the extension study[22,34]; a significantly greater reduction in the mean number of Gb3 inclusion per kidney interstitial capillary than in the placebo group in the migalastat phase III clinical trial[66].
Nonetheless, clearance of inclusions in glomerular podocytes is much more difficult and time-dependent. The largest published study showed that, after a mean of almost 10 years, there was a significant decrease in the Gb3 inclusions in the podocytes both in the so-called “lower fixed dose group” (0.2 mg/Kg/EOW for the entire follow-up) and in the “higher dose group” (doses higher than 0.2 mg/Kg/EOW for, at least, part of the follow-up period), but with a significant correlation between the cumulative dose of ERT received and the clearance of podocyte Gb3; however, GFR only had a significant decrease in the “higher dose group” and remained stable in the “lower fixed dose group”[193].
Nevertheless, the importance of the finding of persistent podocyte Gb3 inclusions remains controversial, because its role as a surrogate biomarker for the progression of renal dysfunction (GFR) in patients treated with ERT is not well established. Notwithstanding the significant correlation between the decrease in urinary albuminuria and the decrease in podocyte Gb3 inclusion score in a long-term evaluation of histological outcomes, in the same cohort, GFR remained stable in all patients, regardless of the decrease in podocyte Gb3 inclusions[18]. Similarly, in the 54-month extension study of the agalsidase β phase III clinical trial, despite persistent inclusion in podocytes in the six evaluated patients, only in one patient, there was a progressive decline in GFR[34]. Moreover, as mentioned above, even in untreated patients, there is no correlation between semi-quantitative scoring systems for intracellular Gb3 inclusions and GFR[9,15,17,191] and there is evidence of heavy podocyte inclusions in patients with late-onset variants, despite the small risk of progressive nephropathy[194,195].
CENTRAL NERVOUS SYSTEM BIOMARKERS
Research for biomarkers of central nervous system (CNS) in FD has been challenging due to the limited knowledge about the physiopathology of CNS involvement in FD. No valuable serum biomarkers exist for the early detection, risk stratification, or monitoring of cerebrovascular disease progression[196]. There is a weak correlation between serum cystatin-C and CNS pathology in males[92]. In females, plasma lyso-GB3 correlates with WML severity[41].
Magnetic resonance imaging
Currently, brain MRI is the most useful tool for evaluating CNS in FD, with several sequences studied as biomarkers of its involvement.
White matter lesions
WML in the form of single, multiple, or confluent hyperintensities in T2-weighted MRI are the most commonly reported image markers of neurovascular involvement in FD patients (present in about 2/3 of the patients, despite the absence of overt clinical signs of cerebral disease)[197,198]. The localization pattern is typical of a small vessel disease and is similar to the age-related WML[199]. Rare in children with FD, the presence and load of WML increase with age, being both genders equally affected[200]. WML load in FD could be modulated by classical and genetic vascular risk factors and the presence of other organ injury, such as cardiomyopathy or nephropathy[201]; however, a recent meta-analysis only found a significant correlation between the load of WML and the risk of stroke, but not with the other organs involvement[202]. The effect of long-term ERT in WML remains controversial, with few studies showing the progression of WML during ERT, but a single study with agalsidase β showed a significantly higher proportion of patients with stabilization or decrease in WML at follow-up in the ERT group in comparison with the placebo group[203-205].
Diffusion tensor imaging and perivascular spaces
Diffusion tensor imaging (DTI) is able to detect early white matter abnormalities and could be a potential marker of disease progression and treatment response, but it needs to be validated in clinical practice; in FD, DTI showed widespread areas of microstructural white matter disruption in Fabry disease (extending beyond WML seen on conventional MRI), with strong correlations with cognition, clinical disease severity, and plasma lyso-Gb3[206-208]. An increase in perivascular spaces, mainly in the basal ganglia, was also demonstrated in FD, suggesting that impaired interstitial fluid drainage might be a mechanism of white matter injury in FD[209].
Basilar artery
Significant enlargement (dolichoectasia) and tortuosity of the intracranial arteries, in particular the basilar artery, are frequently reported in FD patients and distinguish them from controls[210,211]. Furthermore, vertebrobasilar dolichoectasia could be an early marker of neurovascular involvement, being present in 56% of men and 35% of women and identified even in the absence of WML[212].
Pulvinar sign and hippocampus atrophy
Increased signal intensity in the pulvinar region on T1-weighted MRI scans (the pulvinar sign) has been described in patients with FD[213]. Although characteristic, it is not pathognomonic of this disease. It is frequently found in male patients and usually affects both thalamus, although unilateral presentation has been reported. It seems to be present in less than 20% of FD and associated with cardiac and renal dysfunction, but not stroke[214].
Hippocampus atrophy is another CNS image surrogate reported in FD patients (mainly in males) and not associated with ischemic signs, probably reflecting neuronal direct involvement[215]. Moreover, a significant decline in hippocampus volumetry is observed over time and does not correlate with increased WML load or cerebrovascular events[216].
Transcranial Doppler
Transcranial Doppler could also detect abnormalities in brain arteries typical of small vessel disease and abnormal cerebral autoregulation that may be predictive of future neurovascular events in patients with FD[217]. Of note, a study with functional transcranial Doppler revealed cortical vascular dysfunction in the territory of the posterior circulation in asymptomatic patients[196].
SUMMARIZING: WHAT SHOULD WE USE IN THE CLINICAL PRACTICE?
In clinical practice, the aforementioned biomarkers should be used for diagnostic purposes, in the preclinical and clinical evaluation, and to assess treatment response. Figure 2 summarizes the usefulness of the described biomarkers in clinical practice according to these different objectives.
Figure 2. What biomarkers should we use in clinical practice? *not useful in female patients with late-onset phenotype; **characteristic pattern in FD; ***to predict treatment response; Lyso-Gb3: Globotriaosylsphingosine; TDI: tissue Doppler imaging; LGE: late gadolinium enhancement; eGFR: estimated GFR; MRI: magnetic resonance imaging.
SEARCHING FOR NEW BIOMARKERS
Searching for new biomarkers in Fabry disease is paramount, as no proper or well-established plasma or urinary biomarkers are available in clinical practice to aid the diagnosis, early detection of major organ involvement, and monitoring and evaluation of treatment response. However, biomarker discovery remains a very challenging task due to the complexity of the samples (body fluids or tissues) and the wide dynamic range of molecule concentrations in a heterogeneous disease.
There are two main approaches to discovering new plasma/urine biomarkers in FD: “angling”, a one-by-one approach, which involves the study of candidate biomarkers (for example, tubular proteins or inflammatory mediators) where laboratory studies have suggested a pathological link or with proven value in a similar pathological model; “trawling”, based on “omics” medicine, where biological fluid/tissue is screened for disease-associated molecules (for example, proteins or metabolites) using an array of technologies, predominantly based on mass spectrometry.
One-by-one approach has been widely used and several biomarkers with clear pathological correlation have been found. Moreover, the interpretation of the data and correlation with the clinical variables/disease heterogeneity is easier with this approach. However, most of the serum and urine biomarker studies performed to date seem to have converged on a set of proteins and metabolites that are repeatedly identified in many studies and that represent only a small fraction of the entire proteome/metabolome, so the added value of the one-by-one approach in deepening knowledge about the disease pathophysiology is limited[218].
In contrast, omics-based applications use technological resources to further expand our knowledge of the complexities of human disease. However, if reliable and useful inferences with potential for translation into clinical practice are to be achieved, omics techniques require understanding inherent biological variables, rigorous methodology, and analytical chemistry tools, the use of instrumentation that ensures high data quality, and consistent and transparent analysis of the generated data[219]. In proteomics and metabolomics, there are several challenges and limitations that need to be overcome to keep pace with advancements and ultimately realize clinical applicability. These hurdles include the complexity of proteome (a large number of structural and biochemical differences of proteins), a very wide range of protein concentrations, complex sample preparation and data analysis (most reported biomarkers remain unidentified), and limited sensitivity. Additionally, the capacity for quantitative measurements is not yet at the level required for routine diagnostics in a clinical setting. Furthermore, it remains unclear how clinicians will use the sensitive data since even small changes in physiology, such as food ingestion or going up a flight of stairs, can have a significant impact on the metabolome[220].
Despite these limitations, plasma and urinary metabolomics showed that Gb3, lyso-Gb3, and galabiosylceramide isoforms/analogs were elevated in FD patients[47,221-225]. However, these candidate biomarkers still requires validation that they overcome the lyso-Gb3 limitations. This validation includes the evaluation of late-onset females and patients with variants of unknown significance and correlation with clinical manifestations and treatment responses. Thus, properly designed longitudinal studies are warranted.
The proteomic approach has also been applied in the search for biomarkers of FD in plasma, peripheral blood mononuclear cells, and urine. Urinary proteome is the most extensively studied in FD, with a few studies with up to 66 patients reporting several proteins with altered expression[226-231]. A panel of biomarkers including 40 proteins were able to show proteins that are related to early/preclinical phase of FD, to monitoring kidney injury, and to heart involvement; however, the actual prognostic significance of these panels was not clearly depicted and should be evaluated further[231].
Designing studies to identify new biomarkers is also challenging and the design should be tailored to the specific objective of the study/biomarker: diagnostic purposes, identify preclinical involvement, clarify the prognosis, or assess the response to the treatment. Per example, to assess the prognosis and the response to DST, a complex design is warranted [Figure 3]. To identify prognostic biomarkers, several premises should be taken into account in the study design, including longitudinal and prospective design, follow-up duration, and a clear definition of adverse events and disease progression. In studies assessing the response of a specific biomarker to DST, beyond the described aspect, it is paramount to clarify the definitions of treatment response and failure. Defining the duration of a biomarkers study is difficult, because FD is a slowly progressive disorder with a wide spectrum of severity/phenotypes and a low event rate.
Figure 3. Proposed study design to evaluate biomarkers. (A) biomarkers to assess patient prognosis; (B) biomarkers to assess response to treatment.
Several protein and lipid experimental biomarkers are under investigation in Fabry disease [Table 5], mainly related to inflammation, endothelial dysfunction, cardiac fibrosis, glomerulosclerosis, and tubulointerstitial fibrosis. Furthermore, there are also few reports on proteomic and metabolomics analysis.
Experimental biomarkers in Fabry disease
| Biomarkers | Comment | References |
| Inflammatory | C-reactive protein was studied with conflicting results; IL-6 increases in patients with FD cardiomyopathy and decreases during ERT; IL-18 increases even in early stages of FD cardiomyopathy and decreases with ERT; Myeloperoxidase and chitotriosidase only increase in males | [232-235,236,237,238] |
| Coagulation and endothelial dysfunction | Conflicting results, with minimal and inconsistent abnormalities in markers of platelet and coagulation activation; Homocysteine increases in FD and one study reported an increase in all the patients presenting cerebrovascular disease; Nitric oxide metabolism biomarkers seem altered in FD and correlate with cardiomyopathy severity | [239,234,240-243] |
| Vasculopathy | Sphingosine-1-phosphate promotes vascular smooth muscle cell proliferation and correlates with carotid artery intima-media thickness and LV mass index | [244] |
| Myocardial fibrosis | Few studies show an increase in biomarkers of collagen type 1 synthesis and a decrease in matrix metalloproteinases, correlating with LV mass and FD cardiomyopathy progression; Galectin-3 presents a significant increase, even in patients without signs of cardiac involvement, with a significant correlation with LV mass and GFR | [144,245-247] |
| Urinary microscopy | May be a useful tool for the non-invasive assessment of disease progression; it presents some limitations: its diagnostic value is not well established in patients with late-onset phenotypes, most of the findings are not pathognomonic of FD, and its prognostic value needs further evidence | [248] |
| Podocyturia | Podocyte counting in urine sediments is time-consuming and technically challenging to obtain reliable data (reading is observer-dependent). Inconsistent correlations with albuminuria and GFR are found; thus, added value against albuminuria, in terms of diagnostic accuracy, nephropathy prognosis, and response to ERT, has not been established | [249-254] |
| Tubular injury | N-acetyl-β-glucosaminidase presents an inverse correlation with estimated GFR stronger than the one between estimated GFR and albuminuria and is a good predictor of nephropathy progression. Uromodulin and bikunin were studied in small cohorts, with conflicting results | [255-258] |
| Plasma metabolomics | Analogs/isoforms of Gb3 and lyso-Gb3 increase in plasma (to a lesser extent than plasma lyso-Gb3); all of them are significantly more elevated in male patients (compared with female patients) and most of them show a significant decrease during ERT | [47,221,222] |
| Urinary metabolomics | Increased excretion of lyso-Gb3, Gb3, and galabiosylceramide isoforms/analogs (all but one of the lyso-Gb3 analogs has relative concentrations that are higher than lyso-Gb3), with a more prominent increase in male patients and a significant decrease during ERT | [47,223-225] |
| Plasma proteomics | Conflicting results, with different protein profiles found | [259-261] |
| Urinary proteomics | The most consistent alterations found are the up-regulation of prostaglandin H2 D-isomerase and prosaposin (the latter is also observed in pediatric, pre-symptomatic patients); both are known to play roles in processes that might be involved in FD pathophysiology | [226-231] |
| MicroRNAs | Few microRNAs present very good diagnostic accuracy in distinguishing between classical, late-onset phenotypes, and other forms of cardiomyopathy; some correlations with GFR are found | [46,262,263] |
| Circular RNAs | Few circular RNAs are differentially expressed in FD patients and circulating levels are related to the phenotype and disease severity | [264] |
CONCLUSION
The identification of biomarkers for identification of preclinical involvement, prognostic evaluation, and response to treatment is an urgent need in FD. The available biomarkers of total disease burden, such as plasma lyso-Gb3, have several limitations in prognostic evaluation and monitoring treatment response.
Thus, accurate longitudinal studies are needed to identify new biomarkers and their prognostic value. Furthermore, FD has a very complex physiopathology, and certainly, no single biomarker is able to characterize all the pathways involved, so composite scores of clinical and laboratory variables should be the only method to assess each patient’s prognosis and response to treatment.
DECLARATIONS
Authors contributions
The author contributed solely to the article.
Availability of data and materials
My PhD thesis was related to biomarkers in AFD and this similarity is due to my own work.
Financial support and sponsorship
Grant research support from Takeda. Honoraria from Takeda, Sanofi, Biomarin, Ultragenyx, Alexion, Amicus and Chiesi.
Conflicts of interest
The author declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2024.
REFERENCES
1. da Terra Aguiar PR. Early markers of heart and kidney damage in Fabry disease. 2018. Available from: https://core.ac.uk/download/pdf/223237226.pdf [Last accessed on 19 Apr 2024].
2. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89-95.
3. Aerts JM, Kallemeijn WW, Wegdam W, et al. Biomarkers in the diagnosis of lysosomal storage disorders: proteins, lipids, and inhibodies. J Inherit Metab Dis 2011;34:605-19.
4. Linthorst GE, Vedder AC, Aerts JM, Hollak CE. Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta 2005;353:201-3.
5. Froissart R, Guffon N, Vanier MT, Desnick RJ, Maire I. Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma. Mol Genet Metab 2003;80:307-14.
6. Gaspar P, Herrera J, Rodrigues D, et al. Frequency of Fabry disease in male and female haemodialysis patients in Spain. BMC Med Genet 2010;11:19.
7. Gal A, Hughes DA, Winchester B. Toward a consensus in the laboratory diagnostics of Fabry disease - recommendations of a European expert group. J Inher Metab Disea 2011;34:509-14.
8. Smid B, Hollak C, Poorthuis B, et al. Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance. Clin Genet 2015;88:161-6.
9. Branton MH, Schiffmann R, Sabnis SG, et al. Natural history of Fabry renal disease: influence of α-galactosidase a activity and genetic mutations on clinical course. Medicine 2002;81:122-38.
10. Deegan PB, Baehner AF, Barba Romero MA, Hughes DA, Kampmann C, Beck M. European FOS Investigators. Natural history of Fabry disease in females in the Fabry outcome survey. J Med Genet 2006;43:347-52.
11. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry outcome survey. Eur J Clin Invest 2004;34:236-42.
12. Schiffmann R, Warnock DG, Banikazemi M, et al. Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy. Nephrol Dial Transplant 2009;24:2102-11.
13. Matsuzawa F, Aikawa S, Doi H, Okumiya T, Sakuraba H. Fabry disease: correlation between structural changes in alpha-galactosidase, and clinical and biochemical phenotypes. Hum Genet 2005;117:317-28.
14. Echevarria L, Benistan K, Toussaint A, et al. X-chromosome inactivation in female patients with Fabry disease. Clin Genet 2016;89:44-54.
15. Gubler M, Lenoir G, Grünfeld J, et al. Early renal changes in hemizygous and heterozygous patients with Fabry’s disease. Kidney Int 1978;13:223-35.
16. Najafian B, Svarstad E, Bostad L, et al. Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease. Kidney Int 2011;79:663-70.
17. Tøndel C, Bostad L, Hirth A, Svarstad E. Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria. Am J Kidney Dis 2008;51:767-76.
18. Tøndel C, Bostad L, Larsen KK, et al. Agalsidase benefits renal histology in young patients with Fabry disease. J Am Soc Nephrol 2013;24:137-48.
19. Tøndel C, Kanai T, Larsen KK, et al. Foot process effacement is an early marker of nephropathy in young classic Fabry patients without albuminuria. Nephron 2015;129:16-21.
20. Wijburg FA, Bénichou B, Bichet DG, et al. Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial. PLoS One 2015;10:e0124987.
21. Biegstraaten M, Arngrimsson R, Barbey F, et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry working group consensus document. Orphanet J Rare Dis 2015;10:36.
22. Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase a replacement therapy in Fabry’s disease. N Engl J Med 2001;345:9-16.
23. Hughes DA, Elliott PM, Shah J, et al. Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Heart 2008;94:153-8.
24. Schiffmann R, Kopp JB, Austin HA 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 2001;285:2743-9.
25. Eng CM, Banikazemi M, Gordon RE, et al. A phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 2001;68:711-22.
26. Desnick RJ, Dawson G, Desnick SJ, Sweeley CC, Krivit W. Diagnosis of glycosphingolipidoses by urinary-sediment analysis. N Engl J Med 1971;284:739-44.
27. Vedder AC, Linthorst GE, van Breemen MJ, et al. The dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels. J Inherit Metab Dis 2007;30:68-78.
28. Young E, Mills K, Morris P, et al. Is globotriaosylceramide a useful biomarker in Fabry disease? Acta Paediatr Suppl 2005;94:51-4; discussion 37-8.
29. Auray-Blais C, Cyr D, Ntwari A, et al. Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease. Mol Genet Metab 2008;93:331-40.
30. Togawa T, Kodama T, Suzuki T, et al. Plasma globotriaosylsphingosine as a biomarker of Fabry disease. Mol Genet Metab 2010;100:257-61.
31. Smid BE, van der Tol L, Biegstraaten M, Linthorst GE, Hollak CE, Poorthuis BJ. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease. J Med Genet 2015;52:262-8.
32. Whybra C, Kampmann C, Krummenauer F, et al. The mainz severity score index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet 2004;65:299-307.
33. Auray-Blais C, Ntwari A, Clarke JT, et al. How well does urinary lyso-Gb3 function as a biomarker in Fabry disease? Clin Chim Acta 2010;411:1906-14.
34. Germain DP, Waldek S, Banikazemi M, et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol 2007;18:1547-57.
35. Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO. Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting. Nephrol Dial Transplant 2006;21:345-54.
36. Whitfield PD, Calvin J, Hogg S, et al. Monitoring enzyme replacement therapy in Fabry disease-role of urine globotriaosylceramide. J Inherit Metab Dis 2005;28:21-33.
37. Vedder AC, Breunig F, Donker-Koopman WE, et al. Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3. Mol Genet Metab 2008;94:319-25.
38. Popli S, Leehey DJ, Molnar ZV, Nawab ZM, Ing TS. Demonstration of Fabry’s disease deposits in placenta. Am J Obstet Gynecol 1990;162:464-5.
39. Vedder AC, Strijland A, vd Bergh Weerman MA, Florquin S, Aerts JM, Hollak CE. Manifestations of Fabry disease in placental tissue. J Inherit Metab Dis 2006;29:106-11.
40. Aerts JM, Groener JE, Kuiper S, et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci USA 2008;105:2812-7.
41. Rombach SM, Dekker N, Bouwman MG, et al. Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease. Biochim Biophys Acta 2010;1802:741-8.
42. van Breemen MJ, Rombach SM, Dekker N, et al. Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy. Biochim Biophys Acta 2011;1812:70-6.
43. Ouyang y, Chen B, Pan X, et al. Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease. Exper Ther Med 2018;15:3733-42.
44. Azevedo O, Gal A, Faria R, et al. Founder effect of Fabry disease due to p.F113L mutation: clinical profile of a late-onset phenotype. Mol Genet Metab 2020;129:150-60.
45. Duro G, Zizzo C, Cammarata G, et al. Mutations in the GLA Gene and LysoGb3: is it really Anderson-Fabry disease? Int J Mol Sci 2018;19:3726.
46. Aguiar P, Azevedo O, Marino J, Soares JLD, Hughes D. Plasma lyso-Gb3 in Fabry disease: helpful distinguishing phenotypes, but not as predictor of organ involvement. Mol Genet Metab 2019;126:S20.
47. Alharbi FJ, Baig S, Auray-Blais C, et al. Globotriaosylsphingosine (Lyso-Gb3) as a biomarker for cardiac variant (N215S) Fabry disease. J Inherit Metab Dis 2018;41:239-47.
48. Lavalle L, Thomas AS, Beaton B, et al. Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation. PLoS One 2018;13:e0193550.
49. Nowak A, Mechtler TP, Hornemann T, et al. Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease. Mol Genet Metab 2018;123:148-53.
50. Liao HC, Huang YH, Chen YJ, et al. Plasma globotriaosylsphingosine (lysoGb3) could be a biomarker for Fabry disease with a Chinese hotspot late-onset mutation (IVS4+919G>A). Clin Chim Acta 2013;426:114-20.
51. Talbot A, Nicholls K, Fletcher JM, Fuller M. A simple method for quantification of plasma globotriaosylsphingosine: utility for Fabry disease. Mol Genet Metab 2017;122:121-5.
52. Sakuraba H, Togawa T, Tsukimura T, Kato H. Plasma lyso-Gb3: a biomarker for monitoring fabry patients during enzyme replacement therapy. Clin Exp Nephrol 2018;22:843-9.
53. Nowak A, Mechtler TP, Desnick RJ, Kasper DC. Plasma LysoGb3: a useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes. Mol Genet Metab 2017;120:57-61.
54. Baydakova GV, Ilyushkina AA, Moiseev S, et al. α-Galactosidase A/lysoGb3 ratio as a potential marker for Fabry disease in females. Clin Chim Acta 2020;501:27-32.
55. Niemann M, Rolfs A, Störk S, et al. Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet 2014;7:8-16.
56. Ferreira S, Auray-Blais C, Boutin M, et al. Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma. Clin Chim Acta 2015;447:96-104.
57. Sueoka H, Ichihara J, Tsukimura T, Togawa T, Sakuraba H. Nano-LC-MS/MS for quantification of Lyso-Gb3 and its analogues reveals a useful biomarker for Fabry disease. PLoS One 2015;10:e0127048.
58. Spada M, Kasper D, Pagliardini V, Biamino E, Giachero S, Porta F. Metabolic progression to clinical phenotype in classic Fabry disease. Ital J Pediatr 2017;43:1.
59. Rombach SM, van den Bogaard B, de Groot E, et al. Vascular aspects of Fabry disease in relation to clinical manifestations and elevations in plasma globotriaosylsphingosine. Hypertension 2012;60:998-1005.
60. Biegstraaten M, Hollak CE, Bakkers M, Faber CG, Aerts JM, van Schaik IN. Small fiber neuropathy in Fabry disease. Mol Genet Metab 2012;106:135-41.
61. Rombach SM, Aerts JM, Poorthuis BJ, et al. Long-term effect of antibodies against infused alpha-galactosidase a in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome. PLoS One 2012;7:e47805.
62. Effraimidis G, Feldt-Rasmussen U, Rasmussen ÅK, et al. Globotriaosylsphingosine (lyso-Gb3) and analogues in plasma and urine of patients with Fabry disease and correlations with long-term treatment and genotypes in a nationwide female Danish cohort. J Med Genet 2021;58:692-700.
63. Hughes D, Gonzalez D, Maegawa G, et al. Long-term safety and efficacy of pegunigalsidase alfa: a multicenter 6-year study in adult patients with Fabry disease. Genet Med 2023;25:100968.
64. Mauhin W, Lidove O, Amelin D, et al. Deep characterization of the anti-drug antibodies developed in Fabry disease patients, a prospective analysis from the French multicenter cohort FFABRY. Orphanet J Rare Dis 2018;13:127.
65. Arends M, Wijburg FA, Wanner C, et al. Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease. Mol Genet Metab 2017;121:157-61.
66. Germain DP, Hughes DA, Nicholls K, et al. Treatment of Fabry’s disease with the pharmacologic chaperone migalastat. N Engl J Med 2016;375:545-55.
67. Müntze J, Gensler D, Maniuc O, et al. Oral chaperone therapy migalastat for treating Fabry disease: enzymatic response and serum biomarker changes after 1 year. Clin Pharmacol Ther 2019;105:1224-33.
68. Hughes DA, Nicholls K, Shankar SP, et al. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet 2017;54:288-96.
69. Riccio E, Zanfardino M, Ferreri L, et al. Switch from enzyme replacement therapy to oral chaperone migalastat for treating Fabry disease: real-life data. Eur J Hum Genet 2020;28:1662-8.
70. Lenders M, Nordbeck P, Kurschat C, et al. Treatment of Fabry disease management with migalastat-outcome from a prospective 24 months observational multicenter study (FAMOUS). Eur Heart J Cardiovasc Pharmacother 2022;8:272-81.
71. Nowak A, Huynh-Do U, Krayenbuehl PA, Beuschlein F, Schiffmann R, Barbey F. Fabry disease genotype, phenotype, and migalastat amenability: insights from a national cohort. J Inherit Metab Dis 2020;43:326-33.
72. Lenders M, Stappers F, Niemietz C, et al. Mutation-specific Fabry disease patient-derived cell model to evaluate the amenability to chaperone therapy. J Med Genet 2019;56:548-56.
73. Liu HC, Lin HY, Yang CF, et al. Globotriaosylsphingosine (lyso-Gb3) might not be a reliable marker for monitoring the long-term therapeutic outcomes of enzyme replacement therapy for late-onset Fabry patients with the Chinese hotspot mutation (IVS4+919G>A). Orphanet J Rare Dis 2014;9:111.
74. Arends M, Biegstraaten M, Hughes DA, et al. Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: analysis of prognostic factors. PLoS One 2017;12:e0182379.
75. Bichet DG, Aerts JM, Auray-Blais C, et al. Assessment of plasma lyso-Gb3 for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease. Genet Med 2021;23:192-201.
76. Nowak A, Beuschlein F, Sivasubramaniam V, Kasper D, Warnock DG. Lyso-Gb3 associates with adverse long-term outcome in patients with Fabry disease. J Med Genet 2022;59:287-93.
77. Jenab Y, Pourjafari M, Darabi F, Boroumand MA, Zoroufian A, Jalali A. Prevalence and determinants of elevated high-sensitivity cardiac troponin T in hypertrophic cardiomyopathy. J Cardiol 2014;63:140-4.
78. Sato Y, Fujiwara H, Takatsu Y. Cardiac troponin and heart failure in the era of high-sensitivity assays. J Cardiol 2012;60:160-7.
79. Feustel A, Hahn A, Schneider C, et al. Continuous cardiac troponin I release in Fabry disease. PLoS One 2014;9:e91757.
80. Tanislav C, Guenduez D, Liebetrau C, et al. Cardiac troponin I: a valuable biomarker indicating the cardiac involvement in Fabry disease. PLoS One 2016;11:e0157640.
81. Seydelmann N, Liu D, Krämer J, et al. High-sensitivity troponin: a clinical blood biomarker for staging cardiomyopathy in Fabry disease. J Am Heart Assoc 2016;5:e002839.
82. Weidemann F, Beer M, Kralewski M, Siwy J, Kampmann C. Early detection of organ involvement in Fabry disease by biomarker assessment in conjunction with LGE cardiac MRI: results from the SOPHIA study. Mol Genet Metab 2019;126:169-82.
83. Nordin S, Kozor R, Medina-Menacho K, et al. Proposed stages of myocardial phenotype development in Fabry disease. JACC Cardiovasc Imaging 2019;12:1673-83.
84. Nordin S, Kozor R, Baig S, et al. Cardiac phenotype of prehypertrophic Fabry disease. Circ Cardiovasc Imaging 2018;11:e007168.
85. Nordin S, Kozor R, Bulluck H, et al. Cardiac Fabry disease with late gadolinium enhancement is a chronic inflammatory cardiomyopathy. J Am Coll Cardiol 2016;68:1707-8.
86. Augusto JB, Nordin S, Vijapurapu R, et al. Myocardial edema, myocyte injury, and disease severity in Fabry disease. Circ Cardiovasc Imaging 2020;13:e010171.
87. Nordin S, Kozor R, Vijapurapu R, et al. Myocardial storage, inflammation, and cardiac phenotype in Fabry disease after one year of enzyme replacement therapy. Circ Cardiovasc Imaging 2019;12:e009430.
88. Camporeale A, Bandera F, Pieroni M, et al. Effect of migalastat on cArdiac InvOlvement in FabRry DiseAse: MAIORA study. J Med Genet 2023;60:850-8.
89. Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002;105:2392-7.
90. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-7.
91. Coats CJ, Parisi V, Ramos M, et al. Role of serum N-terminal pro-brain natriuretic peptide measurement in diagnosis of cardiac involvement in patients with Anderson-Fabry disease. Am J Cardiol 2013;111:111-7.
92. Torralba-Cabeza MÁ, Olivera S, Hughes DA, Pastores GM, Mateo RN, Pérez-Calvo JI. Cystatin C and NT-proBNP as prognostic biomarkers in Fabry disease. Mol Genet Metab 2011;104:301-7.
93. Liu D, Oder D, Salinger T, et al. Association and diagnostic utility of diastolic dysfunction and myocardial fibrosis in patients with Fabry disease. Open Heart 2018;5:e000803.
94. Bass JL, Shrivastava S, Grabowski GA, Desnick RJ, Moller JH. The M-mode echocardiogram in Fabry’s disease. Am Heart J 1980;100:807-12.
95. Goldman ME, Cantor R, Schwartz MF, Baker M, Desnick RJ. Echocardiographic abnormalities and disease severity in Fabry's disease. J Am Coll Cardiol 1986;7:1157-61.
96. Meucci MC, Lillo R, Del Franco A, et al. Prognostic implications of the extent of cardiac damage in patients with Fabry disease. J Am Coll Cardiol 2023;82:1524-34.
97. Costanzo L, Buccheri S, Capranzano P, et al. Early cardiovascular remodelling in Fabry disease. J Inherit Metab Dis 2014;37:109-16.
98. Fiuza M, Avó LB, Oliveira EI, Gonçalves S, Lopes MG. Detection of preclinical left ventricular dysfunction in Fabry disease: the contribution of tissue Doppler. Rev Port Cardiol 2006;25:613-37.
99. Palecek T, Linhart A, Lubanda JC, et al. Early diastolic mitral annular velocity and color M-mode flow propagation velocity in the evaluation of left ventricular diastolic function in patients with Fabry disease. Heart Vessels 2006;21:13-9.
100. Pieroni M, Chimenti C, Ricci R, Sale P, Russo MA, Frustaci A. Early detection of Fabry cardiomyopathy by tissue Doppler imaging. Circulation 2003;107:1978-84.
101. Toro R, Perez-Isla L, Doxastaquis G, et al. Clinical usefulness of tissue Doppler imaging in predicting preclinical Fabry cardiomyopathy. Int J Cardiol 2009;132:38-44.
102. Zamorano J, Serra V, Pérez de Isla L, et al. Usefulness of tissue Doppler on early detection of cardiac disease in Fabry patients and potential role of enzyme replacement therapy (ERT) for avoiding progression of disease. Eur J Echocardiogr 2011;12:671-7.
103. Sadick N, Thomas L. Cardiovascular manifestations in Fabry disease: a clinical and echocardiographic study. Heart Lung Circ 2007;16:200-6.
104. Graziani F, Laurito M, Pieroni M, et al. Right ventricular hypertrophy, systolic function, and disease severity in Anderson-Fabry disease: an echocardiographic study. J Am Soc Echocardiogr 2017;30:282-91.
105. Hashimoto I, Li X, Hejmadi Bhat A, Jones M, Zetts AD, Sahn DJ. Myocardial strain rate is a superior method for evaluation of left ventricular subendocardial function compared with tissue Doppler imaging. J Am Coll Cardiol 2003;42:1574-83.
106. Morris DA, Blaschke D, Canaan-Kühl S, et al. Global cardiac alterations detected by speckle-tracking echocardiography in Fabry disease: left ventricular, right ventricular, and left atrial dysfunction are common and linked to worse symptomatic status. Int J Cardiovasc Imaging 2015;31:301-13.
107. Gruner C, Verocai F, Carasso S, et al. Systolic myocardial mechanics in patients with Anderson-Fabry disease with and without left ventricular hypertrophy and in comparison to nonobstructive hypertrophic cardiomyopathy. Echocardiography 2012;29:810-7.
108. Saccheri MC, Cianciulli TF, Lax JA, et al. Two-dimensional speckle tracking echocardiography for early detection of myocardial damage in young patients with Fabry disease. Echocardiography 2013;30:1069-77.
109. Shanks M, Thompson RB, Paterson ID, et al. Systolic and diastolic function assessment in fabry disease patients using speckle-tracking imaging and comparison with conventional echocardiographic measurements. J Am Soc Echocardiogr 2013;26:1407-14.
110. Spinelli L, Giugliano G, Imbriaco M, et al. Left ventricular radial strain impairment precedes hypertrophy in Anderson-Fabry disease. Int J Cardiovasc Imaging 2020;36:1465-76.
111. Zada M, Lo Q, Boyd AC, et al. Basal segmental longitudinal strain: a marker of subclinical myocardial involvement in Anderson-Fabry disease. J Am Soc Echocardiogr 2021;34:405-13.e2.
112. Lu DY, Huang WM, Wang WT, et al. Reduced global longitudinal strain as a marker for early detection of Fabry cardiomyopathy. Eur Heart J Cardiovasc Imaging 2022;23:487-95.
113. Réant P, Testet E, Reynaud A, et al. Characterization of Fabry disease cardiac involvement according to longitudinal strain, cardiometabolic exercise test, and T1 mapping. Int J Cardiovasc Imaging 2020;36:1333-42.
114. Lillo R, Graziani F, Panaioli E, et al. Right ventricular strain in Anderson-Fabry disease. Int J Cardiol 2021;330:84-90.
115. Meucci MC, Lillo R, Lombardo A, et al. Comparative analysis of right ventricular strain in Fabry cardiomyopathy and sarcomeric hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2023;24:542-51.
116. Boyd AC, Lo Q, Devine K, et al. Left atrial enlargement and reduced atrial compliance occurs early in Fabry cardiomyopathy. J Am Soc Echocardiogr 2013;26:1415-23.
117. Cheng-Baron J, Chow K, Pagano JJ, et al. Quantification of circumferential, longitudinal, and radial global fractional shortening using steady-state free precession cines: a comparison with tissue-tracking strain and application in Fabry disease. Magn Reson Med 2015;73:586-96.
118. Halfmann MC, Altmann S, Schoepf UJ, et al. Left atrial strain correlates with severity of cardiac involvement in Anderson-Fabry disease. Eur Radiol 2023;33:2039-51.
119. Pichette M, Serri K, Pagé M, Di LZ, Bichet DG, Poulin F. Impaired left atrial function in Fabry disease: a longitudinal speckle-tracking echocardiography study. J Am Soc Echocardiogr 2017;30:170-9.e2.
120. Esposito R, Russo C, Santoro C, et al. Association between left atrial deformation and Brain involvement in patients with Anderson-Fabry disease at diagnosis. J Clin Med 2020;9:2741.
121. Spinelli L, Giugliano G, Pisani A, et al. Does left ventricular function predict cardiac outcome in Anderson-Fabry disease? Int J Cardiovasc Imaging 2021;37:1225-36.
122. Beer M, Weidemann F, Breunig F, et al. Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry’s cardiomyopathy. Am J Cardiol 2006;97:1515-8.
123. Krämer J, Niemann M, Liu D, et al. Two-dimensional speckle tracking as a non-invasive tool for identification of myocardial fibrosis in Fabry disease. Eur Heart J 2013;34:1587-96.
124. Weidemann F, Breunig F, Beer M, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation 2003;108:1299-301.
125. Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation 2009;119:524-9.
126. Semelka RC, Tomei E, Wagner S, et al. Normal left ventricular dimensions and function: interstudy reproducibility of measurements with cine MR imaging. Radiology 1990;174:763-8.
127. Messalli G, Imbriaco M, Avitabile G, et al. Role of cardiac MRI in evaluating patients with Anderson-Fabry disease: assessing cardiac effects of long-term enzyme replacement therapy. Radiol Med 2012;117:19-28.
128. Imbriaco M, Pisani A, Spinelli L, et al. Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: a prospective long-term cardiac magnetic resonance imaging study. Heart 2009;95:1103-7.
129. Koskenvuo JW, Hartiala JJ, Nuutila P, et al. Twenty-four-month alpha-galactosidase a replacement therapy in Fabry disease has only minimal effects on symptoms and cardiovascular parameters. J Inherit Metab Dis 2008;31:432-41.
130. Hazari H, Belenkie I, Kryski A, et al. Comparison of cardiac magnetic resonance imaging and echocardiography in assessment of left ventricular hypertrophy in Fabry disease. Can J Cardiol 2018;34:1041-7.
131. Moon JC, Sachdev B, Elkington AG, et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J 2003;24:2151-5.
132. Hoey ET, Neil-Gallagher E. Utility of gadolinium enhanced cardiovascular MRI to differentiate Fabry’s disease from other causes of hypertrophic cardiomyopathy. Postgrad Med J 2012;88:731-2.
133. Kozor R, Grieve SM, Tchan MC, et al. Cardiac involvement in genotype-positive Fabry disease patients assessed by cardiovascular MR. Heart 2016;102:298-302.
134. De Cobelli F, Esposito A, Belloni E, et al. Delayed-enhanced cardiac MRI for differentiation of Fabry’s disease from symmetric hypertrophic cardiomyopathy. AJR Am J Roentgenol 2009;192:W97-102.
135. Weidemann F, Breunig F, Beer M, et al. The variation of morphological and functional cardiac manifestation in Fabry disease: potential implications for the time course of the disease. Eur Heart J 2005;26:1221-7.
136. Vijapurapu R, Nordin S, Baig S, et al. Global longitudinal strain, myocardial storage and hypertrophy in Fabry disease. Heart 2019;105:470-6.
137. Moon JC, Sheppard M, Reed E, Lee P, Elliott PM, Pennell DJ. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease. J Cardiovasc Magn Reson 2006;8:479-82.
138. Niemann M, Herrmann S, Hu K, et al. Differences in Fabry cardiomyopathy between female and male patients: consequences for diagnostic assessment. JACC Cardiovasc Imaging 2011;4:592-601.
139. Hsu TR, Hung SC, Chang FP, et al. Later onset Fabry disease, cardiac damage progress in silence: experience with a highly prevalent mutation. J Am Coll Cardiol 2016;68:2554-63.
140. Koeppe S, Neubauer H, Breunig F, et al. MR-based analysis of regional cardiac function in relation to cellular integrity in Fabry disease. Int J Cardiol 2012;160:53-8.
141. Deva DP, Hanneman K, Li Q, et al. Cardiovascular magnetic resonance demonstration of the spectrum of morphological phenotypes and patterns of myocardial scarring in Anderson-Fabry disease. J Cardiovasc Magn Reson 2016;18:14.
142. Weidemann F, Niemann M, Herrmann S, et al. A new echocardiographic approach for the detection of non-ischaemic fibrosis in hypertrophic myocardium. Eur Heart J 2007;28:3020-6.
143. Serra VM, Barba MA, Torrá R, et al. Role of cardiac magnetic resonance in cardiac involvement of Fabry disease. Med Clin 2010;135:300-5.
144. Krämer J, Niemann M, Störk S, et al. Relation of burden of myocardial fibrosis to malignant ventricular arrhythmias and outcomes in Fabry disease. Am J Cardiol 2014;114:895-900.
145. Hanneman K, Karur GR, Wasim S, Morel CF, Iwanochko RM. Prognostic significance of cardiac magnetic resonance imaging late gadolinium enhancement in Fabry disease. Circulation 2018;138:2579-81.
146. Hiestand R, Nowak A, Sokolska JM, et al. Clinical and CMR characteristics associated with cardiac events in patients with Fabry disease. Int J Cardiol 2023;382:46-51.
147. Gatterer C, Beitzke D, Graf S, et al. Long-term monitoring of cardiac involvement under migalastat treatment using magnetic resonance tomography in Fabry disease. Life 2023;13:1213.
148. Iles LM, Ellims AH, Llewellyn H, et al. Histological validation of cardiac magnetic resonance analysis of regional and diffuse interstitial myocardial fibrosis. Eur Heart J Cardiovasc Imaging 2015;16:14-22.
149. Ditaranto R, Leone O, Lovato L, et al. Correlations between cardiac magnetic resonance and myocardial histologic findings in Fabry disease. JACC Cardiovasc Imaging 2023;16:1629-32.
150. Pagano JJ, Chow K, Khan A, et al. Reduced right ventricular native myocardial T1 in Anderson-Fabry disease: comparison to pulmonary hypertension and healthy controls. PLoS One 2016;11:e0157565.
151. Pica S, Sado DM, Maestrini V, et al. Reproducibility of native myocardial T1 mapping in the assessment of Fabry disease and its role in early detection of cardiac involvement by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2014;16:99.
152. Sado DM, White SK, Piechnik SK, et al. Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging 2013;6:392-8.
153. Thompson RB, Chow K, Khan A, et al. T1 mapping with cardiovascular MRI is highly sensitive for Fabry disease independent of hypertrophy and sex. Circ Cardiovasc Imaging 2013;6:637-45.
154. Walter TC, Knobloch G, Canaan-Kuehl S, et al. Segment-by-segment assessment of left ventricular myocardial affection in Anderson-Fabry disease by non-enhanced T1-mapping. Acta Radiol 2017;58:914-21.
155. Karur GR, Robison S, Iwanochko RM, et al. Use of myocardial T1 mapping at 3.0 T to differentiate Anderson-Fabry disease from hypertrophic cardiomyopathy. Radiology 2018;288:398-406.
156. van den Boomen M, Slart RHJA, Hulleman EV, et al. Native T1 reference values for nonischemic cardiomyopathies and populations with increased cardiovascular risk: a systematic review and meta-analysis. J Magn Reson Imaging 2018;47:891-912.
157. Roller FC, Fuest S, Meyer M, et al. Assessment of cardiac involvement in Fabry disease (FD) with native T1 mapping. Rofo 2019;191:932-9.
158. Mathur S, Dreisbach JG, Karur GR, et al. Loss of base-to-apex circumferential strain gradient assessed by cardiovascular magnetic resonance in Fabry disease: relationship to T1 mapping, late gadolinium enhancement and hypertrophy. J Cardiovasc Magn Reson 2019;21:45.
159. Camporeale A, Pieroni M, Pieruzzi F, et al. Predictors of clinical evolution in prehypertrophic Fabry disease. Circ Cardiovasc Imaging 2019;12:e008424.
160. Imbriaco M, Nappi C, Ponsiglione A, et al. Hybrid positron emission tomography-magnetic resonance imaging for assessing different stages of cardiac impairment in patients with Anderson-Fabry disease: AFFINITY study group. Eur Heart J Cardiovasc Imaging 2019;20:1004-11.
161. Spinelli L, Imbriaco M, Nappi C, et al. Early Cardiac involvement affects left ventricular longitudinal function in females carrying α-galactosidase a mutation: role of hybrid positron emission tomography and magnetic resonance imaging and speckle-tracking echocardiography. Circ Cardiovasc Imaging 2018;11:e007019.
162. Haga T, Okumura T, Isobe S, et al. Potential prognostic implications of myocardial thallium-201 and iodine-123-beta-methylpentadecanoic acid dual scintigraphy in patients with Anderson-Fabry disease. Ann Nucl Med 2019;33:930-6.
163. Imbriaco M, Pellegrino T, Piscopo V, et al. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease. Eur J Nucl Med Mol Imaging 2017;44:2266-73.
164. Yamamoto S, Suzuki H, Sugimura K, et al. Focal reduction in cardiac 123I-metaiodobenzylguanidine uptake in patients with Anderson-Fabry disease. Circ J 2016;80:2550-1.
165. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 1999;130:461-70.
166. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12.
167. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150. Available from: https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf [Last accessed on 19 Apr 2024].
168. Waldek S, Feriozzi S. Fabry nephropathy: a review - how can we optimize the management of Fabry nephropathy? BMC Nephrol 2014;15:72.
169. Filler G, Bökenkamp A, Hofmann W, Le Bricon T, Martínez-Brú C, Grubb A. Cystatin C as a marker of GFR-history, indications, and future research. Clin Biochem 2005;38:1-8.
170. Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant 2003;18:2024-31.
171. Feriozzi S, Germain DP, Di Vito R, Legrand A, Ricci R, Barbey F. Cystatin C as a marker of early changes of renal function in Fabry nephropathy. J Nephrol 2007;20:437-43.
172. Stevens LA, Coresh J, Schmid CH, et al. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis 2008;51:395-406.
173. Rombach SM, Baas MC, ten Berge IJ, Krediet RT, Bemelman FJ, Hollak CE. The value of estimated GFR in comparison to measured GFR for the assessment of renal function in adult patients with Fabry disease. Nephrol Dial Transplant 2010;25:2549-56.
174. Hopkin RJ, Bissler J, Banikazemi M, et al. Characterization of Fabry disease in 352 pediatric patients in the Fabry registry. Pediatr Res 2008;64:550-5.
175. Ramaswami U, Whybra C, Parini R, et al. Clinical manifestations of Fabry disease in children: data from the Fabry outcome survey. Acta Paediatr 2006;95:86-92.
177. Ries M, Ramaswami U, Parini R, et al. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents. Eur J Pediatr 2003;162:767-72.
178. Ortiz A, Oliveira JP, Waldek S, Warnock DG, Cianciaruso B, Wanner C. Fabry Registry. Nephropathy in males and females with Fabry disease: cross-sectional description of patients before treatment with enzyme replacement therapy. Nephrol Dial Transplant 2008;23:1600-7.
179. Wanner C, Oliveira JP, Ortiz A, et al. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry registry. Clin J Am Soc Nephrol 2010;5:2220-8.
180. Banikazemi M, Bultas J, Waldek S, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 2007;146:77-86.
181. Breunig F, Weidemann F, Strotmann J, Knoll A, Wanner C. Clinical benefit of enzyme replacement therapy in Fabry disease. Kidney Int 2006;69:1216-21.
182. Feriozzi S, Torras J, Cybulla M, Nicholls K, Sunder-Plassmann G, West M. FOS Investigators. The effectiveness of long-term agalsidase alfa therapy in the treatment of Fabry nephropathy. Clin J Am Soc Nephrol 2012;7:60-9.
183. Germain DP, Charrow J, Desnick RJ, et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet 2015;52:353-8.
184. Warnock DG, Ortiz A, Mauer M, et al. Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation. Nephrol Dial Transplant 2012;27:1042-9.
185. West M, Nicholls K, Mehta A, et al. Agalsidase alfa and kidney dysfunction in Fabry disease. J Am Soc Nephrol 2009;20:1132-9.
186. Moura AP, Hammerschmidt T, Deon M, Giugliani R, Vargas CR. Investigation of correlation of urinary globotriaosylceramide (Gb3) levels with markers of renal function in patients with Fabry disease. Clin Chim Acta 2018;478:62-7.
187. Sessa A, Meroni M, Battini G, et al. Renal pathological changes in Fabry disease. J Inherit Metab Dis 2001;24:66-70; discussion 65.
188. Sessa A, Meroni M, Battini G, et al. Renal involvement in Anderson-Fabry disease. J Nephrol 2003;16:310-3.
190. Fischer EG, Moore MJ, Lager DJ. Fabry disease: a morphologic study of 11 cases. Mod Pathol 2006;19:1295-301.
191. Fogo AB, Bostad L, Svarstad E, et al. Scoring system for renal pathology in Fabry disease: report of the international study group of Fabry nephropathy (ISGFN). Nephrol Dial Transplant 2010;25:2168-77.
192. Ortiz A, Oliveira J, Cianciaruso B, Waldek S, Wanner C. The Fabry registry demonstrates heterogeneity of renal progression in 883 males and females with Fabry disease. Nephrol Dial Transplant 2006;21:iv4. Available from: https://www.researchgate.net/publication/295740917_The_Fabry_registry_demonstrates_heterogeneity_of_renal_progression_in_833_males_and_females_with_Fabry_disease [Last accessed on 19 Apr 2024].
193. Skrunes R, Tøndel C, Leh S, et al. Long-term dose-dependent agalsidase effects on kidney histology in Fabry disease. Clin J Am Soc Nephrol 2017;12:1470-9.
194. Santostefano M, Cappuccilli M, Gibertoni D, et al. Fabry disease nephropathy: histological changes with nonclassical mutations and genetic variants of unknown significance. Am J Kidney Dis 2023;82:581-96.e0.
195. Azevedo O, Gago MF, Miltenberger-Miltenyi G, et al. Natural history of the late-onset phenotype of Fabry disease due to the p.F113L mutation. Mol Genet Metab Rep 2020;22:100565.
196. Azevedo E, Mendes A, Seixas D, et al. Functional transcranial Doppler: presymptomatic changes in Fabry disease. Eur Neurol 2012;67:331-7.
197. Buechner S, Moretti M, Burlina AP, et al. Central nervous system involvement in Anderson-Fabry disease: a clinical and MRI retrospective study. J Neurol Neurosurg Psychiatry 2008;79:1249-54.
198. Zhao Y, Zhu Y, Li F, et al. Brain MRI correlations with disease burden and biomarkers in Fabry disease. J Neurol 2023;270:4939-48.
199. Crutchfield KE, Patronas NJ, Dambrosia JM, et al. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology 1998;50:1746-9.
200. Fellgiebel A, Müller MJ, Mazanek M, Baron K, Beck M, Stoeter P. White matter lesion severity in male and female patients with Fabry disease. Neurology 2005;65:600-2.
201. Steinicke R, Gaertner B, Grittner U, et al. Kidney function and white matter disease in young stroke patients: analysis of the stroke in young Fabry patients study population. Stroke 2012;43:2382-8.
202. Körver S, Vergouwe M, Hollak CEM, van Schaik IN, Langeveld M. Development and clinical consequences of white matter lesions in Fabry disease: a systematic review. Mol Genet Metab 2018;125:205-16.
203. Fellgiebel A, Gartenschläger M, Wildberger K, Scheurich A, Desnick RJ, Sims K. Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease. Cerebrovasc Dis 2014;38:448-56.
204. Rombach SM, Smid BE, Bouwman MG, Linthorst GE, Dijkgraaf MG, Hollak CE. Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain. Orphanet J Rare Dis 2013;8:47.
205. Rombach SM, Smid BE, Linthorst GE, Dijkgraaf MG, Hollak CE. Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis: effectiveness of ERT in different disease stages. J Inherit Metab Dis 2014;37:341-52.
206. Kolodny E, Fellgiebel A, Hilz MJ, et al. Cerebrovascular involvement in Fabry disease: current status of knowledge. Stroke 2015;46:302-13.
207. Underhill HR, Golden-Grant K, Garrett LT, Uhrich S, Zielinski BA, Scott CR. Detecting the effects of Fabry disease in the adult human brain with diffusion tensor imaging and fast bound-pool fraction imaging. J Magn Reson Imaging 2015;42:1611-22.
208. Ulivi L, Kanber B, Prados F, et al. White matter integrity correlates with cognition and disease severity in Fabry disease. Brain 2020;143:3331-42.
209. Lyndon D, Davagnanam I, Wilson D, et al. MRI-visible perivascular spaces as an imaging biomarker in Fabry disease. J Neurol 2021;268:872-8.
210. Fellgiebel A, Keller I, Martus P, et al. Basilar artery diameter is a potential screening tool for Fabry disease in young stroke patients. Cerebrovasc Dis 2011;31:294-9.
211. Uçeyler N, Homola GA, Guerrero González H, et al. Increased arterial diameters in the posterior cerebral circulation in men with Fabry disease. PLoS One 2014;9:e87054.
212. Politei J, Schenone AB, Burlina A, et al. Vertebrobasilar dolichoectasia in Fabry disease: the earliest marker of neurovascular involvement? J Inborn Errors Metab Scr 2014;2:232640981454124.
213. Takanashi JI, Barkovich AJ, Dillon WP, Sherr EH, Hart KA, Packman S. T1 hyperintensity in the pulvinar: key imaging feature for diagnosis of Fabry disease. AJNR Am J Neuroradiol 2003;24:916-21.
214. Burlina AP, Manara R, Caillaud C, et al. The pulvinar sign: frequency and clinical correlations in Fabry disease. J Neurol 2008;255:738-44.
215. Fellgiebel A, Wolf DO, Kolodny E, Müller MJ. Hippocampal atrophy as a surrogate of neuronal involvement in Fabry disease. J Inherit Metab Dis 2012;35:363-7.
216. Lelieveld IM, Böttcher A, Hennermann JB, Beck M, Fellgiebel A. Eight-year follow-up of neuropsychiatric symptoms and brain structural changes in Fabry disease. PLoS One 2015;10:e0137603.
217. Segura T, Ayo-Martín O, Gómez-Fernandez I, Andrés C, Barba MA, Vivancos J. Cerebral hemodynamics and endothelial function in patients with Fabry disease. BMC Neurol 2013;13:170.
218. Domon B, Aebersold R. Challenges and opportunities in proteomics data analysis. Mol Cell Proteomics 2006;5:1921-6.
219. Matthews H, Hanison J, Nirmalan N. “Omics”-informed drug and biomarker discovery: opportunities, challenges and future perspectives. Proteomes 2016;4:28.
220. Betzen C, Alhamdani MS, Lueong S, Schröder C, Stang A, Hoheisel JD. Clinical proteomics: promises, challenges and limitations of affinity arrays. Proteomics Clin Appl 2015;9:342-7.
221. Dupont FO, Gagnon R, Boutin M, Auray-Blais C. A metabolomic study reveals novel plasma lyso-Gb3 analogs as Fabry disease biomarkers. Curr Med Chem 2013;20:280-8.
222. Manwaring V, Boutin M, Auray-Blais C. A metabolomic study to identify new globotriaosylceramide-related biomarkers in the plasma of Fabry disease patients. Anal Chem 2013;85:9039-48.
223. Boutin M, Auray-Blais C. Metabolomic discovery of novel urinary galabiosylceramide analogs as Fabry disease biomarkers. J Am Soc Mass Spectrom 2015;26:499-510.
224. Auray-Blais C, Boutin M, Gagnon R, Dupont FO, Lavoie P, Clarke JT. Urinary globotriaosylsphingosine-related biomarkers for Fabry disease targeted by metabolomics. Anal Chem 2012;84:2745-53.
225. Lavoie P, Boutin M, Abaoui M, Auray-Blais C. Fabry disease biomarkers: analysis of urinary lyso-Gb3 and seven related analogs using tandem mass spectrometry. Curr Protoc Hum Genet 2016;90:17.22.1-12.
226. Cuccurullo M, Beneduci A, Anand S, et al. Fabry disease: perspectives of urinary proteomics. J Nephrol 2010;23:S199-212.
227. Kistler AD, Siwy J, Breunig F, et al. A distinct urinary biomarker pattern characteristic of female Fabry patients that mirrors response to enzyme replacement therapy. PLoS One 2011;6:e20534.
228. Manwaring V, Heywood WE, Clayton R, et al. The identification of new biomarkers for identifying and monitoring kidney disease and their translation into a rapid mass spectrometry-based test: evidence of presymptomatic kidney disease in pediatric Fabry and type-I diabetic patients. J Proteome Res 2013;12:2013-21.
229. Matafora V, Cuccurullo M, Beneduci A, et al. Early markers of Fabry disease revealed by proteomics. Mol Biosyst 2015;11:1543-51.
230. Vojtová L, Zima T, Tesař V, et al. Study of urinary proteomes in Anderson-Fabry disease. Ren Fail 2010;32:1202-9.
231. Doykov ID, Heywood WE, Nikolaenko V, et al. Rapid, proteomic urine assay for monitoring progressive organ disease in Fabry disease. J Med Genet 2020;57:38-47.
232. Altarescu G, Chicco G, Whybra C, et al. Correlation between interleukin-6 promoter and C-reactive protein (CRP) polymorphisms and CRP levels with the mainz severity score index for Fabry disease. J Inherit Metab Dis 2008;31:117-23.
233. Kaneski CR, Moore DF, Ries M, Zirzow GC, Schiffmann R. Myeloperoxidase predicts risk of vasculopathic events in hemizgygous males with Fabry disease. Neurology 2006;67:2045-7.
234. Vedder AC, Biró E, Aerts JM, Nieuwland R, Sturk G, Hollak CE. Plasma markers of coagulation and endothelial activation in Fabry disease: impact of renal impairment. Nephrol Dial Transplant 2009;24:3074-81.
235. Yogasundaram H, Nikhanj A, Putko BN, et al. Elevated inflammatory plasma biomarkers in patients with fabry disease: a critical link to heart failure with preserved ejection fraction. J Am Heart Assoc 2018;7:e009098.
236. Chen KH, Chien Y, Wang KL, et al. Evaluation of proinflammatory prognostic biomarkers for Fabry cardiomyopathy with enzyme replacement therapy. Can J Cardiol 2016;32:1221.e1-9.
237. Chien Y, Chien CS, Chiang HC, et al. Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation. Oncotarget 2016;7:87161-79.
238. Vedder AC, Cox-Brinkman J, Hollak CE, et al. Plasma chitotriosidase in male Fabry patients: a marker for monitoring lipid-laden macrophages and their correction by enzyme replacement therapy. Mol Genet Metab 2006;89:239-44.
239. Degraba T, Azhar S, Dignat-george F, et al. Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol 2000;47:229-33.
240. Fedi S, Gensini F, Gori AM, Abbate R, Borsini W. Homocysteine and tissue factor pathway inhibitor levels in patients with Fabry's disease. J Thromb Haemost 2005;3:2117-9.
241. Demuth K, Germain DP. Endothelial markers and homocysteine in patients with classic Fabry disease. Acta Paediatr Suppl 2002;91:57-61.
242. Rohard I, Schaefer E, Kampmann C, Beck M, Gal A. Association between polymorphisms of endothelial nitric oxide synthase gene (NOS3) and left posterior wall thickness (LPWT) of the heart in Fabry disease. J Inherit Metab Dis 2008;31:S349-56.
243. Loso J, Lund N, Avanesov M, et al. Serum biomarkers of endothelial dysfunction in Fabry associated cardiomyopathy. Front Cardiovasc Med 2018;5:108.
244. Brakch N, Dormond O, Bekri S, et al. Evidence for a role of sphingosine-1 phosphate in cardiovascular remodelling in Fabry disease. Eur Heart J 2010;31:67-76.
245. Aguiar P, Azevedo O, Pinto R, et al. Biomarkers of myocardial fibrosis: revealing the natural history of fibrogenesis in Fabry disease cardiomyopathy. J Am Heart Assoc 2018;7:e007124.
246. Aguiar P, Azevedo O, Pinto R, et al. Collagen type I synthesis biomarkers predict the progression of Fabry disease cardiomyopathy. Mol Genet Metab 2018;123:S16.
247. Hernández-Romero D, Sánchez-Quiñones J, Vílchez JA, et al. Galectin-3 and β-trace protein concentrations are higher in clinically unaffected patients with Fabry disease. Sci Rep 2019;9:6235.
248. Riccio E, Sabbatini M, Capuano I, Pisani A. Early biomarkers of Fabry nephropathy: a review of the literature. Nephron 2019;143:274-81.
249. Fall B, Scott CR, Mauer M, et al. Urinary podocyte loss is increased in patients with Fabry disease and correlates with clinical severity of fabry nephropathy. PLoS One 2016;11:e0168346.
250. Pereira EM, Silva AS, Labilloy A, Monte Neto JT, Monte SJ. Podocyturia in Fabry disease. J Bras Nefrol 2016;38:49-53.
251. Selvarajah M, Nicholls K, Hewitson TD, Becker GJ. Targeted urine microscopy in Anderson-Fabry disease: a cheap, sensitive and specific diagnostic technique. Nephrol Dial Transplant 2011;26:3195-202.
252. Trimarchi H, Canzonieri R, Schiel A, et al. Podocyturia is significantly elevated in untreated vs treated Fabry adult patients. J Nephrol 2016;29:791-7.
253. Politei J, Alberton V, Amoreo O, et al. Clinical parameters, LysoGb3, podocyturia, and kidney biopsy in children with Fabry disease: is a correlation possible? Pediatr Nephrol 2018;33:2095-101.
254. Liern M, Collazo A, Valencia M, et al. Podocyturia in pediatric patients with Fabry disease. Nefrología 2019;39:177-83.
255. Aguiar P, Azevedo O, Pinto R, et al. New biomarkers defining a novel early stage of Fabry nephropathy: a diagnostic test study. Mol Genet Metab 2017;121:162-9.
256. Aguiar P, Azevedo O, Pinto R, et al. Tubular dysfunction biomarkers in Fabry disease: better than albuminuria to identify patients at risk of nephropathy progression. Mol Genet Metab 2018;123:S16-7.
257. Vylet'al P, Hůlková H, Zivná M, et al. Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy. J Inherit Metab Dis 2008;31:508-17.
258. Lepedda AJ, Fancellu L, Zinellu E, et al. Urine bikunin as a marker of renal impairment in Fabry's disease. Biomed Res Int 2013;2013:205948.
259. Moore DF, Krokhin OV, Beavis RC, et al. Proteomics of specific treatment-related alterations in Fabry disease: a strategy to identify biological abnormalities. Proc Natl Acad Sci USA 2007;104:2873-8.
260. Heo SH, Kang E, Kim YM, et al. Fabry disease: characterisation of the plasma proteome pre- and post-enzyme replacement therapy. J Med Genet 2017;54:771-80.
261. Hollander Z, Dai DL, Putko BN, et al. Gender-specific plasma proteomic biomarkers in patients with Anderson-Fabry disease. Eur J Heart Fail 2015;17:291-300.
262. Cammarata G, Scalia S, Colomba P, et al. A pilot study of circulating microRNAs as potential biomarkers of Fabry disease. Oncotarget 2018;9:27333-45.
263. Jaurretche S, Perez G, Antongiovanni N, Perretta F, Venera G. Variables associated with a urinary MicroRNAs excretion profile indicative of renal fibrosis in Fabry disease patients. Int J Chronic Dis 2019;2019:4027606.
Cite This Article
Open Access
How to Cite
Aguiar, P. Biomarkers in anderson-Fabry disease: what should we use in the clinical practice?. Rare. Dis. Orphan. Drugs. J. 2024, 3, 13. http://dx.doi.org/10.20517/rdodj.2023.56
Download Citation
Export Citation File:
Type of Import
Tips on Downloading Citation
Citation Manager File Format
Type of Import
Direct Import: When the Direct Import option is selected (the default state), a dialogue box will give you the option to Save or Open the downloaded citation data. Choosing Open will either launch your citation manager or give you a choice of applications with which to use the metadata. The Save option saves the file locally for later use.
Indirect Import: When the Indirect Import option is selected, the metadata is displayed and may be copied and pasted as needed.
About This Article
Special Issue
Copyright
Comments
Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.