2024 Update of the TSOC Expert Consensus of Fabry Disease

Abstract

As an X-linked inherited lysosomal storage disease that is caused by α-galactosidase A gene variants resulting in progressive accumulation of pathogenic glycosphingolipid (Gb3) accumulation in multiple tissues and organs, Fabry disease (FD) can be classified into classic or late-onset phenotypes. In classic phenotype patients, α-galactosidase A activity is absent or severely reduced, resulting in a more progressive disease course with multi-systemic involvement. Conversely, late-onset phenotype, often with missense variants (e.g., IVS4+919G>A) in Taiwan, may present with a more chronic clinical course with predominant cardiac involvement (cardiac subtype), as they tend to have residual enzyme activity, remaining asymptomatic or clinically silent during childhood and adolescence. In either form, cardiac hypertrophy remains the most common feature of cardiac involvement, potentially leading to myocardial fibrosis, arrhythmias, and heart failure. Diagnosis is established through α-galactosidase enzyme activity assessment or biomarker analyisis (globotriaosylsphingosine, Lyso-Gb3), advanced imaging modalities (echocardiography and cardiac magnetic resonance imaging), and genotyping to differentiate FD from other cardiomyopathy. Successful therapeutic response relies on early recognition and by disease awareness from typical features in classic phenotype and cardiac red flags in cardiac variants for timely therapeutic interventions. Recent advances in pharmacological approach including enzyme replacement therapy (agalsidase alfa or beta), oral chaperone therapy (migalastat), and substrate reduction therapy (venglustat) aim to prevent from irreversible organ damage. Genotype- and gender-based monitoring of treatment effects through biomarker (Lyso-Gb3), renal assessment, and cardiac responses using advanced imaging modalities are key steps to optimizing patient care in FD.

Keywords: Cardiac variant; Chaperone; Enzyme replacement therapy; Fabry disease; Globotriaosylceramide; Globotriaosylsphingosine; Heart failure with preserved ejection fraction; IVS4+919G>A; Left ventricular hypertrophy; α-galactosidase A gene.

Figure 1

(A) Typical pathophysiology of FD as a storage disease with cardiac involvement. The figure was adapted and modified from reference . (B) Endomyocardial biopsy from an 86-year-old lady with the cardiac variant of FD (IVS4+919G>A mutation) presenting with left ventricular hypertrophy. Toluidine blue staining demonstrating abundant granular inclusions (white arrows) caused by Gb3 accumulation within cardiomyocytes. (C) Electron microscopy showing enlarged secondary lysosomes packed with lamellated membrane structures (zebra bodies) and myofibrillar loss in cardiomyocytes. CNS, central nervous system; FD, Fabry disease; Gb3, globotriaosylceramide; iNKT, invariant natural killer T; lyso-Gb3, globotriaosylsphingosine; PNS, peripheral nervous system; TLR4, toll-like receptor-4. (Pathology images courtesy of Dr. Tung-Ying Chen, MacKay Memorial Hospital, Division of Pathology.)

Figure 2

(A) Several key galactosidase A (GLA) mutations associated with the classic or late-onset (including cardiac variant) Fabry disease (FD) phenotype, variants of unclear significance (VUS), and benign variants. The triangular shape shows higher frequency of GLA mutations relating benign variants seen during screening but fewer related to Fabry-related clinical manifestations. c.936+919G>A refers to IVS4+919G>A. (B) Disease evolution, proposed stages of FD, age at symptom onset, and cardiac pathophysiology regarding anticipated enzyme replacement treatment (ERT) efficacy. The figure was adapted and modified from references and . CNS, central nervous system; Gb3, globotriaosylceramide; GI, gastrointestinal; LV, left ventricular; LVH, ventricular hypertrophy.

Table 1

Figure 3

Proposed evolution of Fabry disease in cardiac involvement along with clinical progression, electrocardiogram, cardiac imaging, biomarkers, and main populations for diagnosis. The figure was adapted from reference . ECG, electrocardiography; GLS, global longitudinal strain; LGE, late gadolinium enhancement; lyso-Gb3, globotriaosylsphingosine; MBF, myocardial blood flow; NT-proBNP, N terminal pro B type natriuretic peptide. The figure was adapted and modified from reference .

Figure 4

Schematic staging of major cardiac structural and electrical manifestations for the four clinical stages proposed for Fabry disease, together with mechanisms of related myocardial damage and clinical presentations.

Figure 5

(A) Proposed flowchart and red flag signs for the diagnosis of Fabry disease (FD) in patients with idiopathic, unexplained left ventricular hypertrophy (LVH). * Low native non-contrast cardiac magnetic resonance (CMR) imaging T1 values reinforce or raise the suspicion of FD, while normal T1 values do not exclude FD which can occasionally and rarely be seen in untreated patients with mild LVH (mostly females) or in more advanced stage because of “pseudo-normalization”. With normal native T1 values, genetic analysis remains indicated if other clinical findings are supporting FD. ** By lyso-Gb3 level assessment and endomyocardial biopsy. Figure was adapted and modified from reference . (B) Echocardiography including 2D (Left, 4 chamber view) and severely declined global longitudinal strain (-6.8%) (Right, bullseye view) in a 61-year-old man with the cardiac variant of FD (GLA IVS4+919G>A mutation) presenting with clinical heart failure with preserved ejection fraction (HFpEF). (C) In the same patient, CMR imaging showed diffuse myocardial fibrosis in the basal lateral segment using the late gadolinium enhancement (LGE) technique. (D) Native T1 imaging demonstrated low T1 values (888 ± 39 ms) in the early stage of FD. No LVH or LGE was noted. T1 dispersion was 39 ms. (E) Various phenotypes of LVH in patients with FD (CMR imaging courtesy of Dr. Chun-Ho Yun, MacKay Memorial Hospital, Division of Radiology, and Dr. Ling, Kuo, Taipei Veterans General Hospital, Division of Cardiology).

Figure 6

A series of electrocardiography (ECG) changes in a patient with the cardiac variant of Fabry disease (FD) before enzyme replacement therapy. (A) 10 years prior to FD diagnosis: Sinus rhythm without conduction abnormality; (B) 5 years prior to FD diagnosis: PR shortening and incomplete RBBB; (C) 3 years prior to FD diagnosis: ST depression and T wave inversion over lateral and inferior leads; (D) The index date of FD diagnosis: pseudo-normalization of PR interval, RBBB, and left ventricular hypertrophy with strain pattern (ECG courtesy of Dr. Wen-Po Chuang, Division of Cardiology, Far Eastern Memorial Hospital).

Figure 7

Enzyme replacement therapy (ERT) replaces deficient endogenous enzyme with recombinant enzyme. Chaperone therapy binds to and stabilizes amenable gene variants of a-galactosidase A (α-GAL), thereby facilitating proper trafficking of the enzyme to lysosomes and increasing enzyme activity. Substrate reduction therapy inhibits glucosylceramide synthesis and reduces the accumulation of glycosphingolipids, including glucosylceramide and globotriaosylceramide (Gb3). Gene therapies are being developed as a long-term treatment option based on the hypothesis that the targeted cells will overexpress α-GAL and produce functional transgene α-GAL. The figure was adapted from reference .

Figure 8

Flowchart for the management, treatment and follow-up strategy for subjects of confirmed Fabry disease with or without cardiac involvement. Figure was adapted and modified from reference . CMR, cardiac magnetic resonance; CRT, cardiac resynchronization therapy; ECG, electrocardiogram; ERT, enzyme replacement therapy; ETT, exercise treadmill test; ICD, implantable cardioverter-defibrillator; LV, left ventricle; LVOT, left ventricular outflow tract. ^# Detailed recommended monitoring schedule according to TSOC consensus writing committee is presented in Figure 9.

Figure 9

Proposed adult cardiac monitoring “native” schedule by age, sex and genotype (modified from references 14, 19, 126, 143).

Supplemental Figure 1

Display of T1 mapping and measurement for Fabry disease. Calculation of naive and post-contrast T1 values and displayed as bull’s-eye map. Low native T1 value was noted. The patient was acquired CMR imaging one year ago at 3T GE 750 MR scanner and it showed native T1 value 1359 ± 43 ms, which was at the lower limit of normal value at 3T GE 750 MR scanner. Therefore, it is necessary to use same MR scanner to evaluate the change of native T1 value since the normal range of native T1 values are varied.