Fabry disease: Two females with predominant and important cardiac involvement. New mutation for cardiac variant?

Anderson-Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A. The incidence ranges between 1: 40,000 and 1:117,000 of live male births. In Italy, an estimate of incidence is available only for the north-western Italy, where it is of approximately 1:4000. Clinical symptoms include angiokeratomas, corneal dystrophy, and neurological, cardiac and kidney involvement. The prevalence of symptomatic female carriers is about 70%, and in some cases, they can exhibit a severe phenotype. Previous studies suggest a correlation between skewed X chromosome inactivation and symptoms in carriers of X-linked disease, including Fabry disease. In this review, we briefly summarize the disease, focusing on the clinical symptoms of carriers and analysis of the studies so far published in regards to X chromosome inactivation pattern, and manifesting Fabry carriers. Out of 151 records identified, only five reported the correlation between the analysis of XCI in leukocytes and the related phenotype in Fabry carriers, in particular evaluating the Mainz Severity Score Index or cardiac involvement. The meta-analysis did not show any correlation between MSSI or cardiac involvement and skewed XCI, likely because the analysis of XCI in leukocytes is not useful for predicting the phenotype in Fabry carriers.

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Proposed stages of Fabry disease: insights from multiparametric cardiac MRI and advanced ECG

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeaa356.331 ◽

2021 ◽

Vol 22 (Supplement_1) ◽

Author(s):

JA Bicho Augusto ◽

N Johner ◽

D Shah ◽

S Nordin ◽

K Knott ◽

...

Keyword(s):

Fabry Disease ◽

Cardiac Mri ◽

Cardiac Involvement ◽

T2 Mapping ◽

Left Ventricular ◽

P Wave ◽

Stress Perfusion ◽

Healthy Controls ◽

T Wave ◽

Advanced Analysis

Abstract Funding Acknowledgements Type of funding sources: None. Background Staging of Fabry disease (FD) cardiomyopathy uses multiparametric cardiac MRI. Advanced disease is characterized by left ventricular hypertrophy (LVH), myocardial inflammation/oedema (high native T2 mapping) and/or fibrosis (late gadolinium enhancement, LGE). Pre-LVH involvement has been described and includes myocardial sphingolipid storage (low native T1 mapping), impaired LV global longitudinal strain (GLS) and microvascular disease/dysfunction (low stress myocardial blood flow, MBF, in perfusion mapping). We aimed to define (1) the early myocardial phenotype prior to T1 lowering/pre-storage and (2) the stages of cardiac involvement in FD. Methods FD patients and age, sex and heart rate matched healthy controls underwent same-day ECG with advanced analysis and multiparametric CMR (cines, GLS, pre-contrast T1 and T2 mapping, adenosine stress perfusion mapping [for MBF] and LGE). Results 114 Fabry patients (46 ± 13 years, 61% female, 37% [n = 72] had LVH) and 76 controls (49 ± 15 years, 50% female) were included. FD with vs without LVH in brief and as expected, FD with LVH had significantly (p < 0.05) lower MBF, GLS and T1, and higher T2 and %LGE. FD pre-LVH low T1 vs pre-LVH normal T1: low T1 patients (32/72, 44%) had higher LV mass index (67 ± 14 vs 59 ± 10g/m2, P = 0.011), maximum Q wave amplitude (2[1-2] vs 1[1-2]mm, P < 0.001), Sokolow-Lyon index (22[16-28] vs 17[13-23]mm, P = 0.031) and more fractionated QRS complexes (44 vs 18%, P = 0.020). FD pre-LVH normal T1 vs healthy controls: normal T1 pre-LVH Fabry patients (40/72, 56%) had reduced GLS (-18 ± 2 vs -20 ± 2%, P < 0.001), microvascular impairment (lower MBF 2.5 ± 0.7 vs 3.0 ± 0.8mL/g/min, P = 0.028), subtle T2 elevation (50 ± 4 vs 48 ± 2ms, p = 0.027) and limited LGE (%LGE 0.3 ± 1.1 vs 0%, P = 0.004) when compared to healthy controls; ECG abnormalities included shorter P wave duration (88 ± 12 vs 94 ± 15ms, P = 0.010) and T wave peak time (Tonset–Tpeak; 104 ± 28 vs 115 ± 20ms, P = 0.015), resulting in a more symmetric T wave with lower T wave time ratio (Tonset–Tpeak)/(Tpeak–Tend) (1.5 ± 0.4 vs 1.8 ± 0.4, P < 0.001) compared to controls. Conclusion Prior staging of Fabry cardiomyopathy included a pre-LVH stage (accumulation/storage) and two LVH stages (hypertrophy and inflammation; fibrosis and impairment). Here we define an even earlier stage, pre-LVH pre-detectable storage, defined by microvascular dysfunction, impaired GLS and altered atrial depolarization and ventricular repolarization intervals (see Figure). Abstract Figure. Proposed stages of cardiac involvement

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Cardiac involvement in Fabry disease

Giornale di Techniche Nefrologiche e Dialitiche ◽

10.5301/gtnd.2017.17455 ◽

2017 ◽

Vol 29 (1_suppl) ◽

pp. S22-S25

Author(s):

Maurizio Pieroni

Keyword(s):

Fabry Disease ◽

Cardiac Involvement

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New insights for early assessment of cardiac involvement in Anderson-Fabry disease

Journal of Nuclear Cardiology ◽

10.1007/s12350-019-01635-w ◽

2019 ◽

Author(s):

Alberto Cuocolo ◽

Carmela Nappi ◽

Valeria Gaudieri ◽

Antonio Pisani ◽

Massimo Imbriaco

Keyword(s):

Fabry Disease ◽

Cardiac Involvement ◽

Early Assessment

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Increased Spread of Native T1 Values Assessed With MRI as a Marker of Cardiac Involvement in Fabry Disease

American Journal of Roentgenology ◽

10.2214/ajr.20.23102 ◽

2020 ◽

pp. 1-7

Author(s):

Gauri R. Karur ◽

Shobhit Mathur ◽

Chantal F. Morel ◽

Robert M. Iwanochko ◽

Rachel M. Wald ◽

...

Keyword(s):

Fabry Disease ◽

Cardiac Involvement ◽

Native T1

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Enzyme Replacement Therapy in a Case of Anderson–Fabry Disease with Advanced Cardiac Involvement and Malignant Ventricular Arrhythmias

Heart Lung and Circulation ◽

10.1016/j.hlc.2012.05.149 ◽

2012 ◽

Vol 21 ◽

pp. S59

Author(s):

D. Korczyk ◽

J. Hill ◽

C. Denaro ◽

H. Finn

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Ventricular Arrhythmias ◽

Cardiac Involvement ◽

Enzyme Replacement

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Functional capacity and gender-related differences in Fabry disease

European Heart Journal ◽

10.1093/eurheartj/ehab724.1818 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

G Guglielmi ◽

A Mollo ◽

F Bandera ◽

A Camporeale ◽

M Frigelli ◽

...

Keyword(s):

Heart Rate ◽

Fabry Disease ◽

Functional Capacity ◽

Cardiac Involvement ◽

Beta Blockers ◽

Left Ventricular ◽

Lower Percentage ◽

Chronotropic Incompetence ◽

Chronotropic Response ◽

O2 Pulse

Abstract Background Fabry disease (FD) is a rare x-linked lysosomal storage disease characterized by accumulation of glicosphingolipids in several organs, including the heart. Cardiac involvement manifests as left ventricular (LV) hypertrophy, often complicated by myocardial fibrosis. The impact of disease on functional capacity is not well defined, as well as the potential gender-related differences. Aim To evaluate the functional capacity in a cohort of FD patients with different degree of cardiac involvement. Methods Seventy-two patients were prospectively enrolled from March 2015 to December 2019. Patients underwent cardiac magnetic resonance (CMR) and cardiopulmonary exercise test (CPET) with cycle ergometer. In addition to standard CPET parameters, Chronotropic Index (CI) was calculated as (HR max − HR rest) / (HR max predicted − HR rest), adjusting with HR max predicted calculated as 119 + (HR rest/2) − (age/2) in case of beta-blockers treatment. Results CMR showed left ventricle (LV) hypertrophy (LV mass greater than normal reference value) in 36.1% of patients, LGE and reduced T1 values were detected in 30.6% and 59.7% of subjects respectively. Twenty-eight patients were males (39%), the median age was 40 (28–54) [median (25th–75th)] years and only 11 (15%) subjects were on beta-blockers. All subjects performed a maximal test [RQ max = 1.21 (1.14–1.26)] using a ramp protocol of 15 (15–20) Watt. The absolute peakVO2 was 18.2 (15.75–24.08) mL/min/kg, whilst the percentage of predicted peakVO2 was 67.7 (57.3–76.6)%. The chronotropic response of the overall population was characterized by reduced peak heart rate (HRmax) [80.3 (73.8–87.6)% of predicted], and diminished chronotropic index (CI) [0.67 (0.55–0.77) normal value: 0.80], but preserved heart rate reserve (HRR) [21 (12–28) bpm]. Ventilatory efficiency was preserved [VE/VCO2 = 25.70 (23.18–28.00)]. At gender analysis, men showed higher absolute peakVO2 [men vs females: 19.95 (17.20–28.28) vs 17.80 (15.50–21.28) mL/min/kg, p=0.02] but lower percentage of predicted [64.24 (52.58–70.61) vs 70.75 (59.05–78.02)%, p<0.001] than females. No differences between genders were observed in chronotropic response [HRmax = 138 (108–154) vs 142 (135–153) bpm, p=0.38; HRR = 22 (13–36) vs 20 (11–26), p=0.097; CI: 0.67 (0.51–0.76) vs 0.67 (0.58–0.79), p=0.33], whilst females showed a lower peak O2 pulse (VO2/HR) than males [men vs females: 12.08 (10.04–13.64) vs 7.76 (6.88–9.22), p<0.001], possibly related to gender differences in LV dimensions and stroke volume. Conclusions This large cohort of FD patients with different degree of cardiac involvement showed a significantly impaired functional capacity, mainly characterized by relevant chronotropic incompetence (independent from the use of beta-blockers), consistent with systemic autonomic dysfunction. The degree of chronotropic incompetence was similar between the genders, but females showed higher predicted peakVO2 despite a lower peak O2 pulse. FUNDunding Acknowledgement Type of funding sources: None.

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Late diagnsis of Fabry disease at the stage of cardiac involvement

Jounal of arrhythmology ◽

10.35336/va-2021-1-64-67 ◽

2021 ◽

Vol 28 (1) ◽

pp. 64-67

Author(s):

L. N. Malyugina ◽

V. K. Lebedeva ◽

E. A. Osipova ◽

S. V. Moiseev ◽

P. I. Novikov

Keyword(s):

Case Report ◽

Fabry Disease ◽

Clinical Manifestation ◽

Cardiac Arrhythmias ◽

Clinical Case ◽

Cardiac Involvement ◽

Late Diagnosis ◽

Conduction Abnormalities ◽

Classic Phenotype

A clinical case report of late diagnosis (in relation to clinical manifestation) of the classic phenotype of Fabry disease in patient with cardiac involvement: phenocopy of hypertrophy cardiomyopathy, cardiac arrhythmias and conduction abnormalities.

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