Early Risk Stratification for Natural Disease Course in Fabry Patients Using Plasma Globotriaosylsphingosine Levels

Sanne J van der Veen; Mohamed el Sayed; Carla EM Hollak; Marion M Brands; C Khya S Snelder; S Matthijs Boekholdt; Liffert Vogt; Susan MI Goorden; André BP van Kuilenburg; Mirjam Langeveld

doi:10.2215/CJN.0000000000000239

. 2023 Jul 27;18(10):1272–1282. doi: 10.2215/CJN.0000000000000239

Early Risk Stratification for Natural Disease Course in Fabry Patients Using Plasma Globotriaosylsphingosine Levels

Sanne J van der Veen ¹, Mohamed el Sayed ¹, Carla EM Hollak ¹, Marion M Brands ², C Khya S Snelder ¹, S Matthijs Boekholdt ³, Liffert Vogt ⁴, Susan MI Goorden ^5,⁶, André BP van Kuilenburg ^5,⁶, Mirjam Langeveld ^1,^✉

PMCID: PMC10578638 PMID: 37499686

Visual Abstract

graphic file with name cjasn-18-1272-g001.jpg

Keywords: echocardiography, Fabry disease, genetic renal disease

Abstract

Background

Fabry disease is a very heterogeneous X-linked lysosomal storage disease. Disease manifestations in the kidneys, heart, and brain vary greatly, even between patients of the same sex and with the same disease classification (classical or nonclassical). A biomarker with a strong association with the development of disease manifestations is needed to determine the need for Fabry-specific treatment and appropriate frequency of follow-up because clinical manifestations of the disorder may take decennia to develop.

Methods

We investigated the levels of plasma lysoGb3 levels over time and its association with disease manifestations and disease course in 237 untreated patients with Fabry disease (median age 42 years, 38% male) using linear mixed-effect models.

Results

LysoGb3 levels are stable over time in plasma of untreated patients with Fabry disease. Higher levels of lysoGb3 were associated with steeper decline in eGFR (P = 0.05) and a faster increase in albuminuria (measured as the urinary albumin-to-creatinine ratio, P < 0.001), left ventricular mass (measured on echocardiography, P < 0.001), left atrial volume index (P = 0.003), and Fazekas score (P = 0.003). In addition, regardless of age, higher lysoGb3 levels were associated with higher relative wall thickness (P < 0.001) and unfavorable functional markers on echocardiography, including septal mitral annular early diastolic velocity (e′, P < 0.001) and the ratio of early transmitral velocity (E) to e′ (E/e′, P = 0.001).

Conclusions

In an individual patient with Fabry disease, the plasma lysoGb3 level reached a specific level in early childhood which, in the absence of Fabry-specific treatment, remained stable throughout life. The level of lysoGb3 in untreated patients was associated with nearly all Fabry-specific disease manifestations, regardless of the sex of the patient.

Introduction

Fabry disease (Online Mendelian Inheritance in Man 301500) is a rare lysosomal storage disease caused by pathogenic mutations in the α-galactosidase A gene. Depending on the mutation, patients with Fabry disease can either have total or partial deficiency of the α-galactosidase A enzyme, which roughly corresponds with either a classical (more severe) or a nonclassical (attenuated) disease phenotype.¹ Owing to the X-linked inheritance, female patients develop a milder disease phenotype compared with male patients and some female patients can remain without clinical events up to the eighth decade of life.^1,2 Fabry disease can cause a variety of clinical symptoms: left ventricular hypertrophy and myocardial fibrosis resulting in (diastolic) heart failure and arrhythmias,² podocyte loss and fibrosis in the kidneys causing proteinuria and kidney failure,^3,4 and vascular dysfunction leading to transient ischemic attacks and strokes.⁵ Male patients with classical Fabry disease invariably become symptomatic and benefit from early treatment initiation with enzyme replacement therapy.^6–8 Vice versa, starting enzyme replacement therapy in patients with more advanced disease (e.g., with advanced myocardial fibrosis or impaired kidney function) no longer seems to alter disease course.^9–12 However, the remaining patient groups contain both patients at risk for complications as well as those with a (near) normal life expectancy who will develop no or minimal Fabry-related clinical symptoms.^1,2,13 It is unlikely that this last group would significantly benefit from Fabry-specific treatment. This poses an important dilemma; not all patients will develop clinically relevant symptoms of Fabry disease warranting treatment, but those who will become symptomatic seem to benefit from early treatment initiation.⁶ In addition, for patients presenting with new genetic variants and minor and/or nonspecific symptoms, it is not always clear whether the variant is disease-causing or benign, especially in women, in whom enzyme activity can be normal. Therefore, to avoid missing the window of opportunity for treatment, many patients are in routine follow-up to identify early signs of organ manifestations. This results in overmedicalization of patients and inefficiency of clinical care.

The levels of globotriaosylsphingosine (lysoGb3) are strongly associated with both disease type (classical or nonclassical) and sex of the patient.^14,15 LysoGb3 was found to be associated with several disease severity parameters in small studies, including left ventricular mass,^16,17 white matter lesions,¹⁷ and overall disease severity measured using the Mainz Severity Score Index.^14,16,17 Interestingly, even in patients who share the same genetic variant, those with higher lysoGb3 levels were more severely affected compared with those with lower plasma lysoGb3 levels.¹⁶ More recently, high lysoGb3 levels were linked to a higher risk for the development of clinical end points, including KRT, implantable cardioverter-defibrillator/pacemaker implantation, and cerebrovascular events.¹⁸ However, most studies were small and cross-sectional, and some included both treated and untreated patients. It is currently unknown whether plasma lysoGb3 levels are stable throughout life and represent an individual patient trait that can be assessed at any time or whether it increases/decreases with age. In this study, we assessed the stability of lysoGb3 levels in plasma of untreated patients with Fabry disease, we defined optimum cut-off values to classify patients (classical versus nonclassical), and we used linear mixed-effect models to test the relation of plasma lysoGb3 levels to disease manifestations and progression.

Methods

Patients

This study was conducted in accordance with the principles of the Declaration of Helsinki, as revised in 2013. Data were collected retrospectively from clinical records at the Amsterdam University Medical Center (Amsterdam UMC), location AMC, the national referral center for Fabry disease in The Netherlands. All included patients had a confirmed Fabry disease diagnosis, and all patients and/or legal guardian signed informed consent. Data included basic diagnostic data, clinical and biochemical parameters, medication use, and the presence of comorbidities and cardiovascular risk factors. The risk factor “smoking” was scored as present in case of current or former smoking. Obesity was defined as a body mass index >30 kg/m² at the time of lysoGb3 analyses. Hypertension was defined as either a previous diagnosis of hypertension treated with antihypertensive medication or a systolic BP above 140 mm Hg or diastolic BP above 90 mm Hg, measured on at least two occasions.

Patients were classified as having a classical or nonclassical phenotype as previously described by Arends et al.¹ A flow chart used to phenotype classification in clinical practice is included in Supplemental Material 3.

To study the association of plasma lysoGb3 with the natural disease course, only data obtained before the start of enzyme replacement therapy or any other Fabry-specific treatment were included in this study.

Laboratory Measurements

Plasma lysoGb3 (nmol/L) was measured by tandem mass spectrometry, as previously described.¹⁹ This assay measures lysoGb3 (sphingosine d18:1). For reproduction purposes, a detailed description of our assay is included as Supplemental Material 4. Samples were measured on collection as part of our routine clinical practice. All available untreated lysoGb3 values were used to assess stability in individual patients over time. Only the last available untreated value of lysoGb3 was used to assess its association with markers of disease severity. For the sake of visualization only (Figures 1–5), patients were grouped in four different groups. Groups are not included in any of the statistical models. The cutoffs of 2.3 and 40 nmol/L were chosen as they differentiate between classical and nonclassical disease in female and male patients, respectively. In total, 7.3 nmol/L was chosen to split the remaining groups (predominately men with nonclassical Fabry disease and women with classical Fabry disease) into equal halves to visualize the effect within patient groups with the same disease phenotype. A separate table of patient characteristics for each visual group is included in Supplemental Material 2.

**Plasma lysoGb3 levels in patients with Fabry disease with different phenotypes.** Dotted lines represent upper range of normal (0.5 nmol/L), best cut-off value to differentiate between classical and nonclassical Fabry in female patients (2.3 nmol/L) and the best cut-off value to differentiate between classical and nonclassical Fabry in male patients (40). Figure 1 can be viewed in color online at www.cjasn.org.

**Association of plasma lysoGb3 with the progression of white matter lesions (measured using the Fazekas score) on MRI in untreated patients (n=77).** MRI, magnetic resonance imaging. Figure 5 can be viewed in color online at www.cjasn.org.

Glomerular filtration rate was estimated (eGFR) in ml/min per 1.73 m² using serum creatinine and the 2021 Chronic Kidney Disease Epidemiology Collaboration formula.²⁰ Microalbuminuria was assessed using the urinary albumin-to-creatinine ratio (UACR, mg/mmol). In figures, values are depicted in mg/mmol as well as mg/g to enable interpretation worldwide. UACR was determined in a 24-hour urine sample in most cases. If a 24-hour urine sample was not available, measurements were performed in a spot sample. For analyses, UACR was included as a continuous variable. If urinary albumin was below the level of detection, UACR was set to be 0.

The following patients were excluded from the analysis of parameters involving the kidney: patients with a kidney transplantation at the time of presentation (n=5), as well as patients with a confirmed second kidney disease that was considered to be the main reason for the decline in eGFR (n=3, renal artery stenosis, acute glomerulonephritis, and severe bilateral kidney atrophy of uncertain origin).

Echocardiograms

Left ventricular mass index was calculated using the Devereux formula²¹ and was corrected for body surface area using the Dubois formula.²² For the calculation of left ventricular mass index and relative wall thickness, longitudinal data, extracted from clinical echocardiography reports, were used. In a subset of patients (those with at least two echocardiograms with a minimum of 5 years between them), extensive re-evaluation of a large number of echocardiography markers was performed (as part of a different study on the development of cardiac manifestations in Fabry disease) by a single observer (M.e.S.). If Fabry-specific treatment was started between the first and last echocardiogram in this study, only the data of the first echo were used for analysis. From this dataset, we selected the following markers of diastolic dysfunction: e′ (as a marker of diastolic relaxation), E/e′ (as a marker of left atrial filling pressure), and left atrial volume index (LAVI) (as a marker for the duration of elevated LA pressure).

Cerebral Magnetic Resonance Imaging

Cerebral magnetic resonance imaging (MRI) data obtained at our site for a previous study were used; see ref. 13 for more detailed information. All MRI data were obtained using 3 T scanners. Scans were assessed by an independent neuroradiologist blinded for identifying data and scan order. White matter lesions were defined as hyperintensities on axial T2-weighted and fluid-attenuated inversion recovery-weighted imaging without cavitation. Assessment was performed visually using the Fazekas scale.²³ Each scan was given a score between 0 and 6, depending on the severity of white matter lesions at two different locations: periventricular and deep.

Statistics

For statistical analysis and model building, R (version 4.0.3) was used. Optimal cutoffs for phenotyping were determined visually and checked with sensitivity and specificity calculations. All other analyses are performed using linear mixed-effect models correcting for multiple measurements using patient identification (ID) as a random variable (random intercept). A more detailed description of statistics including a markdown file of the complete statistical approach and outcome in R is included in Supplemental Material 5. A complete summary of the analyses and outcomes is presented in Table 1.

Table 1.

Summary of statistical analyses for every included disease manifestation of Fabry disease

Fabry Disease Manifestation	Included Variables in Analyses	Estimate of Effect	Confidence Interval (95%)		P Value
Fabry Disease Manifestation	Included Variables in Analyses	Estimate of Effect	Min	Max	P Value
eGFR, ml/min per 1.73 m ²
Including CMFD^a	_Log10(lysoGb3)	3.64	7.57	13.7	0.49
	Age (yr)	1.04	−1.30	0.79	<0.001^b
	_Log10(lysoGb3)×age	0.24	−0.49	0.006	0.05^b
Excluding CMFD^a	_Log10(lysoGb3)	18.99	1.13	40.1	0.03^b
	Age (yr)	0.80	−1.12	0.47	<0.001^b
	_Log10(lysoGb3)×age	0.57	−0.97	0.16	0.006^b
_Log10 (UACR^c)
Including CMFD^a	_Log10(lysoGb3)	−0.17	0.42	0.08	0.19
	Age (yr)	0.001	−0.008	0.006	0.85
	_Log10(lysoGb3)×age	0.013	0.006	0.019	<0.001^b
Excluding CMFD^a	_Log10(lysoGb3)	0.82	0.204	1.433	0.009^b
	Age (yr)	0.02	0.006	0.026	0.002^b
	_Log10(lysoGb3)×age	0.01	−0.023	0.002	0.09
LVMi, g/m ²
Including CMFD^a	_Log10(lysoGb3)	−2.839	16.23	10.39	0.67
	Age (yr)	0.471	0.077	0.858	0.02^b
	_Log10(lysoGb3)×age	1.022	0.682	1.366	<0.001^b
	Any CV risk factor	11.09	3.760	18.50	0.003^b
Excluding CMFD^a	_Log10(lysoGb3)	−23.61	57.53	10.11	0.17
	Age (yr)	0.075	−0.500	0.643	0.79
	_Log10(lysoGb3)×age	1.582	0.893	2.276	<0.001^b
	Any CV risk factor	12.20	3.834	20.68	0.005^b
RWT
Including CMFD^a	_Log10(lysoGb3)	0.079	0.037	0.120	<0.001^b
	Age (yr)	0.006	0.005	0.007	<0.001^b
	Sex (male)	0.053	−0.102	0004	0.04^b
Excluding CMFD^a	_Log10(lysoGb3)	0.102	0.040	0.163	0.001^b
	Age (yr)	0.006	0.005	0.007	<0.001^b
	Sex (male)	0.045	−0.102	0.011	0.12
e′, cm/s
Excluding CMFD^a	_Log10(lysoGb3)	−2.780	0.209	0.171	<0.001^b
Excluding CMFD^a	Age (yr)	0.190	−3.717	1.844	0.001^b
E/e′
Excluding CMFD^a	_Log10(lysoGb3)	0.176	1.269	5.160	0.001^b
Excluding CMFD^a	Age (yr)	3.212	0.138	0.214	<0.001^b
LAVI, ml/m ²
Excluding CMFD^a	_Log10(lysoGb3)	−18.69	35.61	1.778	0.03^b
	Age (yr)	0.014	−0.266	0.294	0.92
	_Log10(lysoGb3)×age	0.534	0.190	0.879	0.003^b
Fazekas score
Excluding CMFD^a	_Log10(lysoGb3)	−1.612	3.434	0.177	0.08
	Age (yr)	0.011	−0.021	0.043	0.49
	_Log10(lysoGb3)×age	0.062	0.021	0.103	0.003^b

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All analyses are done using linear mixed-effect models correcting for multiple measurements using patient identification as a random variable (random intercept). LysoGb3 was transformed (Log10) to improve fit of the models. For each analysis, the variables “sex” and “presence of cardiovascular risk factors” (e.g., one or more of the following risk factors were present: hypertension, obesity, and smoking) were tested alongside age and individual lysoGb3 values (lysoGb3 was used as a continues variable). Apart from age and lysoGb3 value, only variables that significantly influenced the model (P < 0.05) were included in the final model. When using the estimates, the expected rate of change can be calculated. For example: the left ventricular mass index of a patient with a plasma lysoGb3 value of 1 is expected to increase with 0.78 g/m² every year, compared with a yearly increase of 2.5 g/m² for a patient with a lysoGb3 of 100 nmol/L. CMFD, classical male Fabry patients; UACR, urinary albumin-to-creatinine ratio; LVMi, left ventricular mass indexed to body mass; CV, cardiovascular; RWT, relative wall thickness; e′, mitral annular early diastolic velocity; E/e′, the ratio between early mitral inflow velocity and mitral annular early diastolic velocity; LAVI, left atrial volume index.

To assess if the effect remains after excluding male patients with classical Fabry disease, analyses are performed with and without this group. For some variables, we lacked sufficient data of untreated classical male patients older than 30 years.

P values below 0.05.

Urinary albumin-to-creatinine ratio was measured as mg/mmol before transformation to logscale (log10).

Results

Patient Characteristics

Patient characteristics are presented in Table 2.

Table 2.

Baseline characteristics of the 237 included patients with Fabry disease

	Male (N=89)	Female (N=148)
Disease classification, n (%)
Classical	54 (61)	108 (73)
Nonclassical	35 (39)	40 (27)
Mutatation type, n (%)
Nonsense/frameshift	24 (27)	44 (30)
Missense	60 (67)	98 (66)
Others	4 (5)	6 (4)
Plasma lysoGb3, nmol/L	82 (14–111)	5 (2.4–8.6)
Log10(1+lysoGb3)^a	1.9 (1.2–2.1)	0.8 (0.5–1.0)
Age of last untreated lysoGb3	40 (22–58)	44 (31–54)
Plasma lysoGb3 categories, n (%)^b
<2.3 nmol/L (n=42)	7 (8)	35 (24)
2.3–7.3 nmol/L (n=71)	5 (5)	66 (44)
7.3–40 nmol/L (n=70)	24 (27)	46 (31)
>40 nmol/L (n=54)	53 (60)	1 (1)
Cardiovascular risk factors, n (%)
Smoker (former or current)	38 (43)	57 (39)
Hypertension	22 (25)	32 (22)
Body mass index >30 kg/m²	7 (8)	30 (20)
Any of the above present	50 (56)	82 (55)

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Data are presented as number (percentage) or median and interquartile range, as appropriate.

Missing data: mutation type (n=1), male patient with clear clinical and biochemical Fabry disease characteristics but no mutation found in the coding α-galactosidase A gene sequence; smoking (n=26); hypertension (n=6).

Transformed lysoGb3 values as they are used in the statistical models.

Patients were divided into groups for visualization purposes only. Groups are not included in any of the statistical models.

LysoGb3 Levels over Time

If an individual patient with Fabry disease not treated with Fabry disease–specific therapy, plasma lysoGb3 levels remain stable over time throughout life (Supplemental Material 1). The median follow-up time is 3.7 years (interquartile range [IQR], 1–6 years; range, 0.1–16 years). The exact age at which lysoGb3 stabilizes could not be determined because of the low number of measurements in very young patients.

LysoGb3 and Disease Phenotype

All but one of the 237 patients with Fabry disease had plasma lysoGb3 levels above the reference range (0.3–0.5 nmol/L). One female presented with a genetic α-galactosidase A variant associated with a nonclassical phenotype in her male relatives and a normal plasma lysoGb3 level (0.3 nmol/L). At her last evaluation (aged 39 years), she had no clinical signs or symptoms associated with Fabry disease. Plasma lysoGb3 levels >40 nmol/L separated male patients with classical disease from male patients with nonclassical disease with 98% sensitivity and 100% specificity (P < 0.001, positive predictive value=98%, negative predictive value=100%, Figure 1). Plasma LysoGb3 levels >2.3 nmol/L separated female patients with classical disease from female patients with nonclassical disease with 98% sensitivity and 83% specificity (P < 0.001, positive predictive value=94%, negative predictive value=94%).

LysoGb3 and Kidney Function

Higher lysoGb3 levels were significantly associated with steeper eGFR slopes in all patients with Fabry disease of 18 years and older (n=202, median numbers of measurements two per patient; IQR, 1–5; range, 1–20) (Figure 2A, estimate of _Log10[LysoGb3]×age on eGFR=−0.24, P = 0.05). The association remained statistically significant after removing male patients with classical Fabry from the analyses (estimate of _Log10[LysoGb3]×age=−0.57, P = 0.006).

**Relation between lysoGb3 and the progression of disease manifestations in the kidneys in untreated patients with Fabry disease.** All analyses are performed with actual plasma lysoGb3 levels (after log10 transformation). Grouping is performed for visualization purposes only. (A) Association between plasma lysoGb3 and eGFR slope in untreated patients, the shaded reference area visualizes the approximate 95th percentile eGFR range in healthy individuals, extrapolated from Baba *et al.*²⁴ (B) Association between plasma lysoGb3 levels and progression of albuminuria in untreated patients with Fabry disease. Values are depicted both in mg/mmol (on the left axis) and as mg/g (on the right axis). UACR, urinary albumin-to-creatinine ratio. Figure 2 can be viewed in color online at www.cjasn.org.

Although higher lysoGb3 levels were associated with a faster increase in albuminuria (n=198, median two measurements per patient; range, 1–16) (Figure 2B, estimate of _Log10[LysoGb3]×age on _Log10(UACR)=0.013, P < 0.001), this association was no longer statistically significant after exclusion of classical male patients with Fabry disease (P = 0.09). Adding sex of the patient or the presence of cardiovascular risk factors to either of the models did not affect the outcome.

LysoGb3 and Cardiac Morphology

Higher lysoGb3 levels were significantly associated with a faster increase in left ventricular mass over time on echocardiogram (estimate of _Log10[LysoGb3]×age=1.022, P < 0.001, n=192, median number of measurements: one per patient, IQR, 1–3; range, 1–12; Figure 3A). Aside from lysoGb3 levels, having cardiovascular risk factors (hypertension, smoking, and/or obesity) was an independent risk factor for a higher left ventricular mass index (estimate of effect 11.09, P = 0.003). Using the estimates in Table 1, we can calculate that left ventricular mass of a patient with a plasma lysoGb3 value of 1 increases with 0.78 g/m² every year, compared with a yearly increase of 2.5 g/m² for a patient with a lysoGb3 of 100 nmol/L. Removing male patients with classical Fabry disease from the analyses did not change the outcome (estimate of _Log10[LysoGb3]×age=1.582, P < 0.001 for lysoGb3; estimate=12.20, P = 0.005 for cardiovascular risk factor). Higher lysoGb3 levels are associated with higher relative wall thickness, a sign for concentric remodeling, at any age (estimate of _Log10[LysoGb3]=0.08, P < 0.001, Figure 3B). Removing male patients with classical Fabry disease from the analyses did not change the outcome (estimate of _Log10[LysoGb3]=0.1, P = 0.001).

LysoGb3 and Cardiac Function

We studied the relationship between plasma lysoGb3 levels and functional echocardiography parameters related to heart failure with preserved ejection fraction (HFpEF)²⁶ in 145 patients (median number of measurements per patient 1, range 1–2). Male patients with classical Fabry disease could not be included in these analyses due to lack of data of untreated patients older than 30 years. Higher plasma lysoGb3 levels were significantly related to lower e′ (mitral annular early diastolic velocity, estimate of _Log10[LysoGb3]=−2.8, P < 0.001, Figure 4A) as well as higher E/e′ (the ratio between early mitral inflow velocity and mitral annular early diastolic velocity, estimate of _Log10[LysoGb3]=0.2, P = 0.008, Figure 4B) at any age. No significant association of lysoGb3 on progression over time (slope) for these markers was found. Although these functional parameters give us some insight to the filling pressure at the time the echo is performed, chronic pressure overload results in remodeling of the left atrium and a gradual increase in left atrial volume, which is thus more indicative of the chronic changes. Higher plasma lysoGb3 levels were significantly related to a faster increase in LAVI over time (LAVI, estimate of _Log10[LysoGb3]×age=0.5, P = 0.001).

**Association between plasma lysoGb3 levels and functional parameters on echocardiography in untreated patients with Fabry disease.** (A) Association of plasma lysoGb3 with e′ (P < 0.001). e′ represents the velocity of mitral annular motion during early diastole and is a marker for myocardial relaxation. Patients with higher lysoGb3 values had lower e′ (suggesting stiffer LV) at any age, and there was no difference in slope. (B) Association of plasma lysoGb3 with E/e′ (P < 0.001). E/e′ indicates the ratio between mitral inflow velocity during early diastole (E) and e′ and represents a marker for left atrial filling pressure. Patients with higher lysoGb3 values had higher E/e′ (suggesting higher filling pressure) at any age, and there was no difference in slope. (C) Association of plasma lysoGb3 and LAVI. Higher lysoGb3 levels were associated with a faster increase over time (P = 0.003). The dotted lines in every figure represent the cut-off values for diastolic dysfunction as recommended by the EACVI/ASE.²⁷ In a healthy heart, relaxation of the LV causes a high velocity of the mitral annulus during early diastole (high e′) resulting in blood being “sucked” from the LA into the LV. Under these circumstances, E/e′ is low, usually <8. In the presence of diastolic dysfunction due to LV hypertrophy and stiffening, the LV does not relax properly (e′ becomes lower), and as a result, E/e′ increases. E/e′ >14 is highly suggestive of elevated filling pressures. Chronic elevated pressure in the left atrium results in dilatation, as indicated by an increased LAVI. All analyses are performed with actual plasma lysoGb3 levels (after log10 transformation). LysoGb3 levels are grouped for visualization purposes only as described in the legend. ASE, American Society of Echocardiography; e′, mitral annular early diastolic velocity; E/e′, the ratio between early mitral inflow velocity and mitral annular early diastolic velocity; EACVI, European Association of Cardiovascular Imaging; LA, left atrial; LAVI, left atrial volume index; LV, left ventricle. Figure 4 can be viewed in color online at www.cjasn.org.

LysoGb3 and White Matter Lesions

We studied the association between plasma lysoGb3 levels and Fazekas score (1–6) on cerebral MRI in untreated patients with Fabry disease (n=77, median measurements two per patient; IQR, 1–4; range, 1–7). Higher plasma lysoGb3 levels were significantly associated with a faster increase in white matter lesions over time (Figure 5, estimate of _Log10[LysoGb3]×age=0.06, P = 0.003).

Discussion

We show, for the first time, that plasma lysoGb3 remains stable over decades in patients with Fabry disease (Supplemental Material 1). In addition, we show that plasma lysoGb3 levels are associated with severity and/or progression of nearly all measured Fabry disease manifestations. Combined, these findings suggest that plasma lysoGb3 reaches a stable level in childhood and indicates which disease burden can be expected later in life. This is in contrast to Gb3 accumulation in, for example, podocytes, which has been shown to slowly increase over time.²⁸

Fabry disease is a slowly progressive disease, and children/young adults do not always show clinical signs of the disorder. Our data suggest that measuring plasma lysoGb3 at the time of diagnosis could help assess the expected natural disease course in an individual patient, irrespective of the age at diagnosis. The strict association of plasma lysoGb3 with disease type—regardless of the age of analysis—further supports this observation (Figure 1,^14,17,29,30). In fact, we showed that plasma lysoGb3 levels can differentiate between the classical and nonclassical phenotype with very high accuracy and could thus be used as the decisive parameter to determine the disease type in an individual with a genetic variant of unknown significance.

We confirmed the reverse association of plasma lysoGb3 with decline in kidney function (Figure 3A,^14,16) and verified that this association was not mainly driven by male patients with the classical disease type (who are known to have more kidney involvement compared with patients with the other phenotypes). A similar effect was found for albuminuria: Higher lysoGb3 levels in plasma were associated with a faster increase in UACR (Figure 2B). The strongest association is between plasma lysoGb3 levels and increase in left ventricular mass (Figure 3A,^16,17). In non-Fabry patients, left ventricular hypertrophy is strongly associated with overall mortality, myocardial infarction, and stroke.³¹ In patients with Fabry disease, a higher left ventricular mass index on echocardiography was also associated with higher clinical event rate.⁹ A new finding is the association of plasma lysoGb3 with markers of diastolic dysfunction, measured by echocardiography (e′, E/e′ and LAVI). This is particularly relevant because HFpEF, the clinical syndrome caused by diastolic dysfunction, is a major cause of heart failure in patients with Fabry disease,³² and heart failure is currently the leading cause of symptoms and death in patients with Fabry disease.² In many other diseases, higher e′, E/e′, and LAVI values are strongly associated with premature mortality and increased occurrence of clinical cardiac end points.^33–36 The associations indicate that lysoGb3 does not only have a relationship with cardiac morphology but also with cardiac function and the risk of developing HFpEF. Finally, we found that higher lysoGb3 levels were associated with a faster progression of white matter lesions in the brain on MRI.

A drawback of this study is that it is carried in retrospection. This represents the real-world situation in which many patients were started on treatment and long-term data of newly diagnosed patients left untreated are simply not available. Strictly speaking, this makes our dataset unfit to be used for prediction modeling. However, we showed the stability of lysoGb3 in individual (untreated) patients, suggesting that the measured lysoGb3 value represents a static individual Fabry disease trait, which justifies its use in prognostication.

We confirmed that in patients with lysoGb3 levels below 2.3 nmol/L (normal reference range 0.3–0.5), kidney function remains within the normal range (Figure 1) and cardiac morphologic and functional parameters show slow progression over time and become abnormal only late in life (from the seventh decade of life onward, Figures 3 and 4). These findings are consistent with earlier observations that the risk of cardiovascular complications in female patients with a nonclassical disease type (in whom lysoGb3 levels are usually below 2.3 nmol/L) is low, and if they do occur, it is late in life.² The seven male (nonclassical) patients with Fabry disease with lysoGb3 levels below 2.3 in this study showed a similar clinical course. In our opinion, this group is unlikely to benefit from Fabry-specific therapy and may not even require routine follow-up before the sixth decade of life. Within the group of patients with a plasma lysoGb3 between 2.3 and 40 nmol/L (mostly male patients with nonclassical Fabry disease and female patients with classical Fabry disease), measuring plasma lysoGb3 gives additional insight into the expected clinical course. In patients with relatively low lysoGb3 levels and no or minor clinical Fabry disease manifestations, prolonging the interval between clinical evaluations seems justified, and in our opinion, the potential effect of treatment should be weighed against the burden of lifelong infusions. In patients with higher lysoGb3 levels, more rigorous follow-up is warranted and treatment may be started with less restraint. Further multicenter studies are needed to confirm these findings and identify other biomarkers to improve clinical risk stratification of patients with Fabry disease.

On the basis of the results from this study, we propose measuring plasma lysoGb3 at the time of diagnosis to help diagnose and classify Fabry disease. In addition, the early stabilization of lysoGb3 in plasma over time makes it a suitable marker to help determine the needed frequency of follow-up and the timing of treatment initiation in asymptomatic patients.

Supplementary Material

cjasn-18-1272-s001.png^{(361.1KB, png)}

Open in a new tab

Footnotes

A.B.P.v.K. and M.L. are co-senior authors.

Disclosures

M.M. Brands reports research funding from Intrabio and serving as principal investigator at the Amsterdam site for the study: N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC). M. el Sayed is involved in a premarketing study with Indorses; all financial arrangements are made through AMC Research BV. CH.E. Hollak and M. Langeveld are involved in premarketing studies with Genzyme, Idorsia, and Protalix. S.J. van der Veen was involved in premarketing studies with Chiesi/Protalix; financial arrangements were made through AMC Research BV. A.B.P. van Kuilenburg reports research funding from Biosidus. L. Vogt reports consultancy for AstraZeneca Netherlands, Bayer BV Netherlands, and Vifor Pharma Netherlands; research funding from Dutch Kidney Foundation and Health Holland; and role as an Associate Editor of BMC Nephrology. All remaining authors have nothing to disclose.

Funding

S.J. van der Veen: Sphinx, The Amsterdam Lysosome Center.

Author Contributions

Conceptualization: Mirjam Langeveld, Sanne J. van der Veen.

Data curation: Mohamed el Sayed, C. Khya S. Snelder, Sanne J. van der Veen.

Formal analysis: Sanne J. van der Veen.

Methodology: Susan M.I. Goorden, Sanne J. van der Veen.

Supervision: Mirjam Langeveld, André B.P. van Kuilenburg.

Visualization: Sanne J. van der Veen.

Writing – original draft: Sanne J. van der Veen.

Writing – review & editing: S. Matthijs Boekholdt, Marion M. Brands, Mohamed el Sayed, Susan M.I. Goorden, Carla E.M. Hollak, Mirjam Langeveld, C. Khya S. Snelder, André B.P. van Kuilenburg, Liffert Vogt.

Supplemental Material

This article contains the following supplemental material online at http://links.lww.com/CJN/B791.

Supplemental Material 1. Stability of plasma lysoGb3 over time in individual untreated patients.

Supplemental Material 2. Alternative representation of patient characteristics.

Supplemental Material 3. Current flow chart used to diagnose and phenotype Fabry disease at the AUMC.

Supplemental Material 4. Detailed procedure of lab GMD (Amsterdam UMC) lysoGb3 assay.

Supplemental Material 5. Markdown file of statistical analyses performed in R.

References

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5.Tuttolomondo A Pecoraro R Simonetta I, et al. Neurological complications of Anderson-Fabry disease. Curr Pharm Des. 2013;19(33):6014–6030. doi: 10.2174/13816128113199990387 [DOI] [PubMed] [Google Scholar]
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7.Spada M Baron R Elliott PM, et al. The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease - a systematic literature review by a European panel of experts. Mol Genet Metab. 2019;126(3):212–223. doi: 10.1016/j.ymgme.2018.04.007 [DOI] [PubMed] [Google Scholar]
8.Tondel C Bostad L Larsen KK, et al. Agalsidase benefits renal histology in young patients with Fabry disease. J Am Soc Nephrol. 2013;24(1):137–148. doi: 10.1681/ASN.2012030316 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.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(8):e0182379. doi: 10.1371/journal.pone.0182379 [DOI] [PMC free article] [PubMed] [Google Scholar]
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11.Banikazemi M Bultas J Waldek S, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007;146(2):77–86. doi: 10.7326/0003-4819-146-2-200701160-00148 [DOI] [PubMed] [Google Scholar]
12.Weidemann F Niemann M Stork S, et al. Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications. J Intern Med. 2013;274(4):331–341. doi: 10.1111/joim.12077 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Korver S Longo MGF Lima MR, et al. Determinants of cerebral radiological progression in Fabry disease. J Neurol Neurosurg Psychiatry. 2020;91(7):756–763. doi: 10.1136/jnnp-2019-322268 [DOI] [PubMed] [Google Scholar]
14.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(2):148–153. doi: 10.1016/j.ymgme.2017.07.002 [DOI] [PubMed] [Google Scholar]
15.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(4):262–268. doi: 10.1136/jmedgenet-2014-102872 [DOI] [PubMed] [Google Scholar]
16.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(4):e0193550. doi: 10.1371/journal.pone.0193550 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.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(9):741–748. doi: 10.1016/j.bbadis.2010.05.003 [DOI] [PubMed] [Google Scholar]
18.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(3):287–293. doi: 10.1136/jmedgenet-2020-107338 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Gold H Mirzaian M Dekker N, et al. Quantification of globotriaosylsphingosine in plasma and urine of fabry patients by stable isotope ultraperformance liquid chromatography-tandem mass spectrometry. Clin Chem. 2013;59(3):547–556. doi: 10.1373/clinchem.2012.192138 [DOI] [PubMed] [Google Scholar]
20.Inker LA Eneanya ND Coresh J, et al. New creatinine- and cystatin C–based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737–1749. doi: 10.1056/nejmoa2102953 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Lang RM Bierig M Devereux RB, et al. Recommendations for chamber quantification. Eur J Echocardiogr. 2006;7(2):79–108. doi: 10.1016/j.euje.2005.12.014 [DOI] [PubMed] [Google Scholar]
22.Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916;17(6_2):863–871. doi: 10.1001/archinte.1916.00080130010002 [DOI] [PubMed] [Google Scholar]
23.Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Am J Roentgenol. 1987;149(2):351–356. doi: 10.2214/ajr.149.2.351 [DOI] [PubMed] [Google Scholar]
24.Baba M Shimbo T Horio M, et al. Longitudinal study of the decline in renal function in healthy subjects. PLoS One. 2015;10(6):e0129036. doi: 10.1371/journal.pone.0129036 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Lang RM Badano LP Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1–39.e14. doi: 10.1016/j.echo.2014.10.003 [DOI] [PubMed] [Google Scholar]
26.Pieske B Tschope C de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40(40):3297–3317. doi: 10.1093/eurheartj/ehz641 [DOI] [PubMed] [Google Scholar]
27.Nagueh SF Smiseth OA Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American society of echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277–314. doi: 10.1016/j.echo.2016.01.011 [DOI] [PubMed] [Google Scholar]
28.Najafian B, Tondel C, Svarstad E, Gubler MC, Oliveira JP, Mauer M. Accumulation of globotriaosylceramide in podocytes in fabry nephropathy is associated with progressive podocyte loss. J Am Soc Nephrol. 2020;31(4):865–875. doi: 10.1681/ASN.2019050497 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.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(2):239–247. doi: 10.1007/s10545-017-0127-2 [DOI] [PubMed] [Google Scholar]
30.Niemann M Rolfs A Stork S, et al. Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet. 2014;7(1):8–16. doi: 10.1161/circgenetics.113.000249 [DOI] [PubMed] [Google Scholar]
31.Bouzas-Mosquera A, Broullon FJ, Alvarez-Garcia N, Peteiro J, Mosquera VX, Castro-Beiras A. Association of left ventricular mass with all-cause mortality, myocardial infarction and stroke. PLoS One. 2012;7(9):e45570. doi: 10.1371/journal.pone.0045570 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Pieroni M Moon JC Arbustini E, et al. Cardiac involvement in fabry disease: JACC review topic of the week. J Am Coll Cardiol. 2021;77(7):922–936. doi: 10.1016/j.jacc.2020.12.024 [DOI] [PubMed] [Google Scholar]
33.Sharp AS Tapp RJ Thom SA, et al. Tissue Doppler E/E' ratio is a powerful predictor of primary cardiac events in a hypertensive population: an ASCOT substudy. Eur Heart J. 2010;31(6):747–752. doi: 10.1093/eurheartj/ehp498 [DOI] [PubMed] [Google Scholar]
34.Saito C, Minami Y, Haruki S, Arai K, Ashihara K, Hagiwara N. Prognostic relevance of a score for identifying diastolic dysfunction according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr. 2022;35(5):469–476. doi: 10.1016/j.echo.2021.12.006 [DOI] [PubMed] [Google Scholar]
35.Ozbek BT Modin D Mogelvang R, et al. Echocardiographic predictors of long-term adverse cardiovascular outcomes in participants with and without diabetes mellitus: a follow-up analysis of the Copenhagen City Heart Study. Diabet Med. 2021;38(10):e14627. doi: 10.1111/dme.14627 [DOI] [PubMed] [Google Scholar]
36.Behera MK Swain SN Sahu MK, et al. Diastolic dysfunction is a predictor of poor survival in patients with decompensated cirrhosis. Int J Hepatol. 2021; eCollection 2021:1–8. doi: 10.1155/2021/5592376 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B1] 1.Arends M Wanner C Hughes D, et al. Characterization of classical and nonclassical fabry disease: a multicenter study. J Am Soc Nephrol. 2017;28(5):1631–1641. doi: 10.1681/ASN.2016090964 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B2] 2.El Sayed M Hirsch A Boekholdt M, et al. Influence of sex and phenotype on cardiac outcomes in patients with Fabry disease. Heart. 2021;107(23):1889–1897. doi: 10.1136/heartjnl-2020-317922 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B3] 3.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(6):663–670. doi: 10.1038/ki.2010.484 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B4] 4.Sanchez-Nino MD Sanz AB Carrasco S, et al. Globotriaosylsphingosine actions on human glomerular podocytes: implications for Fabry nephropathy. Nephrol Dial Transplant. 2011;26(6):1797–1802. doi: 10.1093/ndt/gfq306 [DOI] [PubMed] [Google Scholar]

[B5] 5.Tuttolomondo A Pecoraro R Simonetta I, et al. Neurological complications of Anderson-Fabry disease. Curr Pharm Des. 2013;19(33):6014–6030. doi: 10.2174/13816128113199990387 [DOI] [PubMed] [Google Scholar]

[B6] 6.van der Veen SJ Korver S Hirsch A, et al. Early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression. Mol Genet Metab. 2022;135(2):163–169. doi: 10.1016/j.ymgme.2021.12.004 [DOI] [PubMed] [Google Scholar]

[B7] 7.Spada M Baron R Elliott PM, et al. The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease - a systematic literature review by a European panel of experts. Mol Genet Metab. 2019;126(3):212–223. doi: 10.1016/j.ymgme.2018.04.007 [DOI] [PubMed] [Google Scholar]

[B8] 8.Tondel C Bostad L Larsen KK, et al. Agalsidase benefits renal histology in young patients with Fabry disease. J Am Soc Nephrol. 2013;24(1):137–148. doi: 10.1681/ASN.2012030316 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B9] 9.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(8):e0182379. doi: 10.1371/journal.pone.0182379 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B10] 10.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(2):157–161. doi: 10.1016/j.ymgme.2017.05.001 [DOI] [PubMed] [Google Scholar]

[B11] 11.Banikazemi M Bultas J Waldek S, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007;146(2):77–86. doi: 10.7326/0003-4819-146-2-200701160-00148 [DOI] [PubMed] [Google Scholar]

[B12] 12.Weidemann F Niemann M Stork S, et al. Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications. J Intern Med. 2013;274(4):331–341. doi: 10.1111/joim.12077 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B13] 13.Korver S Longo MGF Lima MR, et al. Determinants of cerebral radiological progression in Fabry disease. J Neurol Neurosurg Psychiatry. 2020;91(7):756–763. doi: 10.1136/jnnp-2019-322268 [DOI] [PubMed] [Google Scholar]

[B14] 14.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(2):148–153. doi: 10.1016/j.ymgme.2017.07.002 [DOI] [PubMed] [Google Scholar]

[B15] 15.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(4):262–268. doi: 10.1136/jmedgenet-2014-102872 [DOI] [PubMed] [Google Scholar]

[B16] 16.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(4):e0193550. doi: 10.1371/journal.pone.0193550 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B17] 17.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(9):741–748. doi: 10.1016/j.bbadis.2010.05.003 [DOI] [PubMed] [Google Scholar]

[B18] 18.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(3):287–293. doi: 10.1136/jmedgenet-2020-107338 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B19] 19.Gold H Mirzaian M Dekker N, et al. Quantification of globotriaosylsphingosine in plasma and urine of fabry patients by stable isotope ultraperformance liquid chromatography-tandem mass spectrometry. Clin Chem. 2013;59(3):547–556. doi: 10.1373/clinchem.2012.192138 [DOI] [PubMed] [Google Scholar]

[B20] 20.Inker LA Eneanya ND Coresh J, et al. New creatinine- and cystatin C–based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737–1749. doi: 10.1056/nejmoa2102953 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B21] 21.Lang RM Bierig M Devereux RB, et al. Recommendations for chamber quantification. Eur J Echocardiogr. 2006;7(2):79–108. doi: 10.1016/j.euje.2005.12.014 [DOI] [PubMed] [Google Scholar]

[B22] 22.Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916;17(6_2):863–871. doi: 10.1001/archinte.1916.00080130010002 [DOI] [PubMed] [Google Scholar]

[B23] 23.Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Am J Roentgenol. 1987;149(2):351–356. doi: 10.2214/ajr.149.2.351 [DOI] [PubMed] [Google Scholar]

[B24] 24.Baba M Shimbo T Horio M, et al. Longitudinal study of the decline in renal function in healthy subjects. PLoS One. 2015;10(6):e0129036. doi: 10.1371/journal.pone.0129036 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B25] 25.Lang RM Badano LP Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1–39.e14. doi: 10.1016/j.echo.2014.10.003 [DOI] [PubMed] [Google Scholar]

[B26] 26.Pieske B Tschope C de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40(40):3297–3317. doi: 10.1093/eurheartj/ehz641 [DOI] [PubMed] [Google Scholar]

[B27] 27.Nagueh SF Smiseth OA Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American society of echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277–314. doi: 10.1016/j.echo.2016.01.011 [DOI] [PubMed] [Google Scholar]

[B28] 28.Najafian B, Tondel C, Svarstad E, Gubler MC, Oliveira JP, Mauer M. Accumulation of globotriaosylceramide in podocytes in fabry nephropathy is associated with progressive podocyte loss. J Am Soc Nephrol. 2020;31(4):865–875. doi: 10.1681/ASN.2019050497 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B29] 29.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(2):239–247. doi: 10.1007/s10545-017-0127-2 [DOI] [PubMed] [Google Scholar]

[B30] 30.Niemann M Rolfs A Stork S, et al. Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet. 2014;7(1):8–16. doi: 10.1161/circgenetics.113.000249 [DOI] [PubMed] [Google Scholar]

[B31] 31.Bouzas-Mosquera A, Broullon FJ, Alvarez-Garcia N, Peteiro J, Mosquera VX, Castro-Beiras A. Association of left ventricular mass with all-cause mortality, myocardial infarction and stroke. PLoS One. 2012;7(9):e45570. doi: 10.1371/journal.pone.0045570 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B32] 32.Pieroni M Moon JC Arbustini E, et al. Cardiac involvement in fabry disease: JACC review topic of the week. J Am Coll Cardiol. 2021;77(7):922–936. doi: 10.1016/j.jacc.2020.12.024 [DOI] [PubMed] [Google Scholar]

[B33] 33.Sharp AS Tapp RJ Thom SA, et al. Tissue Doppler E/E' ratio is a powerful predictor of primary cardiac events in a hypertensive population: an ASCOT substudy. Eur Heart J. 2010;31(6):747–752. doi: 10.1093/eurheartj/ehp498 [DOI] [PubMed] [Google Scholar]

[B34] 34.Saito C, Minami Y, Haruki S, Arai K, Ashihara K, Hagiwara N. Prognostic relevance of a score for identifying diastolic dysfunction according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr. 2022;35(5):469–476. doi: 10.1016/j.echo.2021.12.006 [DOI] [PubMed] [Google Scholar]

[B35] 35.Ozbek BT Modin D Mogelvang R, et al. Echocardiographic predictors of long-term adverse cardiovascular outcomes in participants with and without diabetes mellitus: a follow-up analysis of the Copenhagen City Heart Study. Diabet Med. 2021;38(10):e14627. doi: 10.1111/dme.14627 [DOI] [PubMed] [Google Scholar]

[B36] 36.Behera MK Swain SN Sahu MK, et al. Diastolic dysfunction is a predictor of poor survival in patients with decompensated cirrhosis. Int J Hepatol. 2021; eCollection 2021:1–8. doi: 10.1155/2021/5592376 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Early Risk Stratification for Natural Disease Course in Fabry Patients Using Plasma Globotriaosylsphingosine Levels

Sanne J van der Veen

Mohamed el Sayed

Carla EM Hollak

Marion M Brands

C Khya S Snelder

S Matthijs Boekholdt

Liffert Vogt

Susan MI Goorden

André BP van Kuilenburg

Mirjam Langeveld

Visual Abstract

Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Patients

Laboratory Measurements

Figure 1.

Figure 5.

Echocardiograms

Cerebral Magnetic Resonance Imaging

Statistics

Table 1.

Results

Patient Characteristics

Table 2.

LysoGb3 Levels over Time

LysoGb3 and Disease Phenotype

LysoGb3 and Kidney Function

Figure 2.

LysoGb3 and Cardiac Morphology

Figure 3.

LysoGb3 and Cardiac Function

Figure 4.

LysoGb3 and White Matter Lesions

Discussion

Supplementary Material

Footnotes

Disclosures

Funding

Author Contributions

Supplemental Material

References

ACTIONS

PERMALINK

RESOURCES

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