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Cardiac manifestations in patients with classical or cardiac subtype of Fabry disease

Wang, Wei-Tinga,c; Sung, Shih-Hsiena,c; Liao, Jo-Nana,c; Hsu, Ting-Rongb,c; Niu, Dau-Mingb,c; Yu, Wen-Chunga,c,*

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Journal of the Chinese Medical Association: September 2020 - Volume 83 - Issue 9 - p 825-829
doi: 10.1097/JCMA.0000000000000379
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Fabry disease (FD), a genetic disease initially described in 1898, is an X-linked lysosomal storage disorder induced by a deficiency of the enzyme α-galactosidase A (α-GLA); a deficiency of α-GLA results in systemic accumulation of glycolipids, particularly globotriaosylsphingosine (Gb3), in multiple organs, including the cardiac, neural, and renal systems.1,2 The estimated incidence of FD ranges from 1 in 40,000 to 1 in 117,000 worldwide.3 Patients with classic FD show <1% α-galactosidase activity and typically present with symptoms such as neuropathic pain, cornea verticillata, and angiokeratoma right from their childhood or adolescence. Manifestations including hypertrophic cardiomyopathy, cardiac rhythm disturbance, progressive renal failure, and stroke constitute the long-term indications of FD.4 In Taiwan, a high incidence of a cardiac subtype of FD with a special mutation (IVS4 919G>A) was discovered after newborn screening.5 Its manifestations include concentric left ventricular hypertrophy (LVH), valvular involvement, and arrhythmias in the fifth to eighth decades of life, with minimal extracardiac involvement. However, the question as to whether the severity of cardiac involvement differs between these two types of FD remains unclear. Accordingly, we conducted this study to investigate this question by using echocardiographic findings, amino-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels, and the Mainz Severity Score Index (MSSI). MSSI is a clinical scoring system that is used to analyze the severity of FD and monitor its clinical course in response to enzyme replacement therapy (ERT).6


We performed the study in accordance with the guidelines of the Declaration of Helsinki. The protocols were approved by an institutional review board and written informed consent was obtained from patients before participation.

We enrolled consecutive patients with classic FD (n = 22; median age, 47.0 [32.75–56.25] years; men, 72.7%); we also selected age- and sex-matched patients with the cardiac subtype of FD from our cohort of patients with the IVS4 + 919G>A mutation (n = 22; median age, 49.5 [33.75–57.0] years; men, 72.7%). FD was diagnosed on the basis of clinical symptoms/signs and pedigree screening of index case, plasma α-galactosidase activity, and molecular analysis of GLA. All female patients demonstrated heterozygous mutations, with five, one, and four of them showing normal range of α-galactosidase activity, classic FD, and cardiac subtype of FD, respectively.

We recorded data on clinical characteristics, including signs and symptoms, biochemical tests, and echocardiography findings, before the patients underwent ERT. Because the most common presentation, LVH, is usually symptomless initially, the disease duration is not precise, particularly in the cardiac subtype. Therefore, we used age-matched patients in this study to ensure the same duration of enzyme deficiency in both groups and thus minimize potential bias.

The MSSI cardiovascular score was used to assess disease severity. MSSI comprises four components that cover the general, neurological, cardiovascular, and renal signs and symptoms of FD. Different specialists, including a dermatologist, neurologist, ophthalmologist, and cardiologist, recorded a detailed medical history of and performed clinical investigations on the patients. The maximum MSSI score for the general and renal components is 18, and that for the neurological and cardiovascular components is 20. The sum of the scores for these individual components constitutes the total MSSI score. The severity of FD can be divided into three categories according to the total MSSI score: mild, <20; moderate, 20–40; and severe, >40.6

According to the recommendations of the American Society of Echocardiography, we measured left ventricular parameters, including left ventricular mass (LVM), diastolic interventricular septal thickness, systolic and diastolic left ventricular internal diameter, and diastolic left ventricular posterior wall thickness, by using serial two-dimensional guided M-mode echocardiography.7,8 LVM was calculated using the American Society of Echocardiography simplified cubed equation.

All results are reported as median (25th–75th percentile) and numbers (%). Variables were compared using the Wilcoxon rank-sum test or Pearson’s χ2 test, as appropriate. Statistical analyses were performed using SPSS version 19.0 (SPSS, Chicago, IL, USA). Statistical significance was set at p < 0.05.


Table 1 presents the baseline characteristics of the patients in the two groups. The patients were adequately matched for age and sex. Comorbidities, including hypertension, diabetes mellitus, and dyslipidemia, showed similar distributions between the classic FD and cardiac subtype groups; however, the frequency of smoking was higher in the cardiac subtype group (classic type vs cardiac subtype: 4.5% vs 18.2%; p = 0.039). Moreover, blood pressure levels were similar between the two groups; nevertheless, the resting heart rate was higher in the cardiac subtype group (classic type vs cardiac subtype: median, 59.6 [25th–75th percentile: 55.8–62.6] vs 64.9 [25th–75th percentile: 58.7–75.2]; p = 0.025). No significant differences existed between the two groups in terms of renal function parameters, lipid profile, or NT-pro-BNP levels. Table 2 lists cardiac structure and function indices investigated using echocardiography, including the left ventricular dimension in the end diastolic and systolic phases, left ventricular septal and posterior wall thickness, ejection fraction, LVM, left atrial dimension, pulmonary arterial systolic pressure, and tricuspid annular plane systolic excursion; we noted that these indices were comparable between the two groups. One patient in each group underwent permanent pacemaker implantation.

Table 1 - Baseline characteristics of patients with classical type vs cardiac subtype
Demographic data Classical subjects N = 22 Cardiac subjects N = 22 p
N (%) N (%)
Age (y) 47.0 (32.75–56.25) 49.5 (33.75–57.0) 0.655
 Male 16 (72.7) 16 (72.7) 1.000
 Female 6 (27.3) 6 (27.3)
Laboratory data
 Systolic BP (mmHg) 114.0 (105.5–128.25) 120.5 (106.0–146.75) 0.291
 Diastolic BP (mmHg) 68.5 (64.125–71.625) 74.5 (63.5–86.0) 0.093
  Heart rate 59.6 (55.8–62.6) 64.9 (58.7–75.2) 0.025
  Blood urea nitrogen 12.0 (11.0–16.25) 15.0 (13.0–16.0) 0.247
  Creatinine 0.81 (0.65–0.9475) 0.81 (0.68–0.98) 0.979
 eGFR (mL/min/1.73 m2) 83.6 (59.8–112.2) 86.1 (66.4–102.3) 0.937
 Cholesterol (mg/dL) 184.0 (140.0–244.0) 187.0 (155.5–198.0) 0.490
 Triglyceride (mg/dL) 79 (53.0–152.0) 127.5 (74.25–226.0) 0.117
 HDL-cholesterol (mg/dL) 55.5 (52.75–59.0) 50.0 (44.5–60.5) 0.163
 LDL-cholesterol (mg/dl) 113.5 (82.0–149.5) 104.0 (88.5–127.0) 0.546
 NT-proBNP (pg/mL) 145.8 (24.71–1341) 42.7 (19.2–156.4) 0.316
 Hypertension 9 (40.9) 10 (45.5) 0.223
 Diabetes mellitus 1 (4.5) 2 (9.1) 0.554
 Dyslipidemia 5 (22.7) 1 (4.5) 0.082
 Smoking 1 (4.5) 4 (18.2) 0.039
The data were presented as median (25th percentile–75th percentile).
BP = blood pressure; eGFR = estimated glomerular filtration rate; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NT-proBNP = N-terminal pro-Brain Natriuretic Peptide.

Table 2 - Echocardiographic findings of patients with classical type vs cardiac subtype
Demographic data Classical subjects N = 22 Cardiac subjects N = 22 p
Echocardiographic findings
 Aortic root (mm) 26.5 (26.0–30.0) 29.0 (26.0–30.25) 0.171
 IVSTd (mm) 11.0 (9.0–14.0) 10.0 (8.0–13.25) 0.645
 PWTd (mm) 11.5 (10.0–13.0) 10.5 (8.0–13.75) 0.554
 LVIDd (mm) 45.0 (41.0–49.25) 45.5 (41.25–50.25) 0.503
 LVIDs (mm) 26.0 (23.0–32.0) 27.5 (25.0–32.0) 0.823
 LVEDV (mL) 90.0 (74.0–116.0) 96.0 (77.5–120.0) 0.883
 LVESV (mL) 25.0 (18.0–44.0) 30.0 (22.5–39.0) 0.376
 LVEF (%) 70.0 (66.75–75.25) 68.0 (60.5–73.8) 0.496
 LV mass (g) 191.5 (130.5–246.75) 154.0 (121.5–225.0) 0.882
 LV mass index (g/m2) 115.8 (81.5–138.5) 90.1 (66.9–133.9) 0.918
 Left atrium (mm) 34.0 (30.75–36.5) 32.8 (27.0–36.5) 0.417
 PASP (mmHg) 24.0 (21.0–29.0) 22.0 (13.0–25.0) 0.053
 TAPSE (mm) 2.0 (2.0–3.0) 2.0 (2.0–2.0) 0.221
IVSTd = interventricular septum thickness in end-diastole; PWTd = posterior wall thickness in enddiastole; LVIDd = left ventricular internal dimension in end-diastole; LVIDs = left ventricular internal dimension in end-systole; LVEDV = left ventricular end-diastole volume; LVESV = left ventricular endsystole volume; LVEF = left ventricular ejection fraction; PASP = pulmonary arterial systolic pressure; TAPSE = tricuspid annular plane systolic excursion.

The total MSSI score was significantly higher for the classic FD group compared with the cardiac subtype group. This was because the classic FD group had higher scores for the general (classic type vs cardiac subtype; median, 1.0 [25th–75th percentile: 0.0–3.0] vs 0.0 [25th–75th percentile: 0.0–1.0]; p = 0.001), neurological (classic type vs cardiac subtype: median, 5.0 [25th–75th percentile: 0.0–6.0] vs 0.0 [25th–75th percentile: 0.0–1.5]; p = 0.002), and renal (classic type vs cardiac subtype: median, 4.0 [25th–75th percentile: 0.0–4.0] vs 0.0 [25th–75th percentile: 0.0–0.0]; p = 0.007) components. The scores for the cardiovascular component did not differ significantly between the two groups (classic type vs cardiac subtype: median, 10.0 [25th–75th percentile: 2.0–12.5] vs 10.5 [25th–75th percentile: 9.0–15.25]; p = 0.277; Table 3 and Figure 1).

Table 3 - Mainz Severity Score Index of patients with classical type vs cardiac subtype
Demographic data Classical subjects N = 22 Cardiac subjects N = 22 p
General score 1.0 (0.0–3.0) 0.0 (0.0–1.0) 0.001
 Characteristic facial 0 (0) 0 (0) 1.000
 Angiokeratoma 2 (9.1) 0 (0) 0.148
 Edema 2 (9.1) 0 (0) 0.148
 Musculoskeletal 4 (18.2) 0 (0) 0.036
 Cornea verticillata 7 (31.8) 0 (0) 0.004
 Diaphoresis 0.060
  Hypo/hyperhidrosis 1 (4.5) 0 (0)
  Anhidrosis 4 (18.2) 0 (0)
 Abdominal pain 1 (4.5) 0 (0) 0.312
 Diarrhea/constipation 1 (4.5) 0 (0) 0.312
 Hemorrhoids 0 (0) 0 (0) 1.000
 Pulmonary 2 (9.1) 1 (4.5) 0.550
 NYHA 0.769
  Class I 4 (18.2) 6 (27.3)
  Class II 1 (4.5) 1 (4.5)
  Class III 0 (0) 0 (0)
  Class IV 0 (0) 0 (0)
Neurologic score 5.0 (0.0–6.0) 0.0 (0.0–1.5) 0.002
 Tinnitus 0 (0) 1 (4.5) 0.312
 Vertigo 2 (9.1) 1 (4.5) 0.550
  Occasional 6 (27.3) 3 (13.6) <0.001
  Chronic 9 (40.9) 0 (0)
 Fever pain crisis 4 (18.2) 0 (0) 0.036
 Cerebrovascular 0 (0) 2 (9.1) 0.148
  Depression 0 (0) 0 (0) 1.000
  Fatigue 1 (4.5) 1 (4.5) 1.000
  Reduced activity level 0 (0) 2 (9.1) 0.148
Cardiovascular score 10.0 (2.0–12.5) 10.5 (9.0–15.25) 0.277
 Left ventricle hypertrophy
  Thickening of wall 1 (4.5) 0 (0) 0.197
  LVH seen in ECG 3 (13.6) 0 (0)
  Cardiomyopathy (<15 mm) 9 (40.9) 11 (50)
  Severe cardiomyopathy (>15 mm) 4 (18.2) 8 (36.4)
 ECG abnormalities 13 (59.1) 11 (50) 0.545
 Hypertension 9 (40.9) 13 (59.1) 0.228
 Valve insufficiency 20 (90.9) 19 (86.4) 0.635
 Pacemaker 1 (4.5) 1 (4.5) 1.000
Renal score 4.0 (0.0–4.0) 0.0 (0.0–0.0) 0.007
 Proteinuria 10 (45.5) 3 (13.6) 0.021
 Low GFR 2 (9.1) 1 (4.5) 0.550
 Creatinine > 3.5 mg/dL 0 (0) 0 (0) 1.000
 Dialysis 1 (4.5) 0 (0) 0.312
Total score 17.5 (13.25–23.0) 14.5 (9.75–18.0) 0.051
We expressed the individual parameter with number (percentage) for categorical variables and median (25th percentile–75th percentile) for numerical variables.
GFR = glomerular filtration rate; LVH = left ventricular hypertrophy.

Fig. 1
Fig. 1:
Cardiovascular subscore of the Mainz Severity Score Index (MSSI) in patients with classic and cardiac subtypes of Fabry disease. The error bars represent standard deviation.

Regarding the general component, the classic FD group exhibited a higher prevalence of cornea verticillata (classic type vs cardiac subtype, 7 [31.8] vs 0 [0]; p = 0.004) and musculoskeletal disorders (classic type vs cardiac subtype, 4 [18.2] vs 0 [0]; p = 0.036). Furthermore, concerning the neurological component, the classic FD group had a higher prevalence of acroparesthesia (classic type vs cardiac subtype, 15 [68.2] vs 3 [13.6]; p < 0.001) and fever/pain crisis (classic type vs cardiac subtype, 4 [18.2] vs 0 [0]; p = 0.036). Regarding the renal component, the classic FD group exhibited more severe proteinuria (classic type vs cardiac subtype, 10 [45.5] vs 3 [13.6]; p = 0.021).


Our study’s most noteworthy finding is that cardiovascular manifestations were similar between the classic and cardiac subtype of FD according to echocardiographic findings, NT-pro-BNP levels, and MSSI scores.

FD is an X-linked lysosomal storage disorder resulting from a deficiency of the enzyme α-GLA, which leads to a systemic accumulation of glycolipids in major organs, particularly in the vascular endothelium and smooth muscle cells of the renal and cardiovascular systems.9,10 Classic symptoms observed in hemizygous male patients include acroparesthesia, angiokeratoma, hypohidrosis, corneal opacities, and dysfunction of the kidney, brain, and heart. The cardiac manifestations of FD include LVH,11 valvular involvement,12 and arrhythmias,13 which usually present in the fifth to eighth decades of life. Atypical variants of FD that occur because of residual low levels of α-GLA activity, resulting in a “milder” and later-onset phenotype,14 are being increasingly recognized. We demonstrated that the degrees of severity of cardiac manifestations were similar between the classic FD and cardiac subtype groups, as indicated by echocardiographic findings and MSSI scores. A previous study revealed that the MSSI score is a highly specific tool for distinguishing FD from other severe afflictions and that it could be used to evaluate disease severity.6 The severity of FD (MSSI) is significantly correlated with age.15,16

The increasing frequency of later-onset mutations detected through neonatal screening may render FD a broad cardiovascular problem that extends beyond childhood. In general, cardiac manifestations of FD, such as arrhythmia, angina, and LVH, are considered to result from Gb3 accumulation in the sinoatrial node, conduction system, vascular endothelium, and cardiomyocytes. Moreover, the more severe the α-Gal A defect is, the more severe the clinical manifestations are and the earlier the disease onset becomes. Our findings suggest that Gb3 accumulation is not the only factor determining the clinical symptoms of FD.17 A previous study revealed that glycolipid accumulation in the myocardium constitutes only 1%–3% of the total mass in a hypertrophic heart.18 Other pathogenic factors such as inflammatory cytokines19–22and oxidative stress may also contribute to clinical manifestations.19,23–25

With the availability of ERT as a possible treatment, cardiac disease has become the leading cause of death in patients with FD.26,27 Improvement in renal care and early initiation of ERT can reduce the impact of renal disease as a cause of death in patients with FD.28,29 Previous research reported that early ERT also led to favorable outcomes in patients with Fabry cardiomyopathy.30 Moreover, a study indicated that late diagnosis was a factor for early death in patients with FD.27 Although the level of cardiac involvement in the cardiac subtype of FD is similar to that in classic FD, the cardiac subtype of FD is usually diagnosed late because of minimal extracardiac involvement.31 Therefore, early diagnosis, careful evaluation of disease progression, and early initiation of therapy might be crucial to improve the outcomes of patients with FD of the cardiac subtype.

This study has some limitations. First, our sample size was small because of the limited number of patients with classic FD. The rare nature of the disease contributed to the small sample size, although we included all consecutive cases of classic FD. Second, classic FD is usually diagnosed early because of extracardiac manifestations. However, we chose age- and sex-matched patients with cardiac subtype of FD to reduce potential confounding factors.

In conclusion, our results demonstrate no significant differences between the classic and cardiac subtypes of FD in terms of echocardiographic findings or MSSI cardiovascular scores. Therefore, we suggest that the levels of severity of cardiac involvement are similar in both subtypes of FD. These findings should be considered in the clinical evaluation and treatment of FD.


This study was supported in part by intramural grants from the Taipei Veterans General Hospital (Grant No. V101C-187, V103C-166, and V104C-175) and grants in aid from the Research Foundation of Cardiovascular Medicine, (100-01-010), Taipei, Taiwan.


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Anderson–Fabry disease; Cardiac variant; Transthoracic echocardiography

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