INTRODUCTION

Fabry disease (FD), also known as Anderson-FD, is a rare X-linked (Xq22) lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Reduction or absence of lysosomal enzyme α-galactosidase A activity results in glycosphingolipids accumulation in cells throughout the body affecting multiple organs.[1] Due to the X-linked character, male patients experience an earlier onset and a more severe course of disease. FD was reported in approximately 1% of patients with left ventricular hypertrophy (LVH) on echocardiography or a hypertrophic cardiomyopathy (HCM) phenotype.[2] Confirmation of FD is made by enzyme activity assay and genetic testing. There is no or very low α-galactosidase A activity in patients with the classic phenotype of FD, resulting in early onset of the disease and progressive multisystemic involvement.[3] For those patients who are cardiac or renal variants have a later disease onset,[3] studies show that FD can significantly reduce life expectancy by approximately 20 years in males and 15 years in females.[4] In the heart, glycosphingolipids accumulate in the vascular endothelial cells, smooth muscle cells, cardiomyocytes, conduction system cells, and valvular fibroblasts.[1] Cardiac involvement is frequent in the classic phenotype and late-onset cardiac variant (in isolation without extracardiac manifestation). Primary cardiac manifestations include the development of LVH with or without heart failure symptoms, conduction abnormalities, arrhythmias, angina, valvular dysfunction, and uncommonly sudden cardiac death. Specific enzyme replacement therapy (ERT) has been shown to clear glycosphingolipids from the vascular endothelium and stabilize cardiac mass growth. [1] Therefore, timely diagnosis with early initiation of ERT leads to favorable outcomes.[1]

CARDIAC MRI IN FD

Cardiac magnetic resonance imaging (MRI) is a crucial imaging modality for the quantitative and qualitative assessment of FD cardiomyopathy. Apart from monitoring disease progress, cardiac MRI also helps early disease detection in cases of mild form or subclinical cardiac phenotypes.[3] Characteristics of FD cardiomyopathy include progressive left ventricular wall thickening, ventricular dysfunction, microvascular angina, arrhythmias and valvular heart disease, and patients eventually progress to systolic dysfunction and heart failure over decades of life.[3] Some female patients can also develop diastolic dysfunction and myocardial fibrosis without LVH.[5] In advanced stage of disease, left ventricular thinning and aneurysm formation are also seen.[1] It can be difficult to distinguish FD cardiomyopathy from other forms of unexplained LVH, especially in the absence of extracardiac manifestations in atypical FD patients and heterozygous females.[3] Therefore, it is important to consider FD as a potential cause of unexplained LVH.[3] Three stages of cardiac involvement in FD have been proposed by Nordin et al. as follows: The accumulation phase (normal or low native T1 mapping without LVH) [Figure 1a-d]; the inflammation and myocyte hypertrophy phase (low native T1 mapping, presence of late gadolinium enhancement (LGE) with or without LVH); and the fibrosis and impairment phase (pseudonormalization of native T1 mapping and extensive LGE).[6]

Figure 1: A 46-year-old male patient with known Fabry disease diagnosed 6 years ago. (a) The initial MRI shows diffusely decreased T1 value (883ms*) of left ventricle myocardium with no evidence of left ventricular hypertrophy nor late gadolinium enhancement. (b) Interval MRI shows asymmetrical left ventricular hypertrophy relatively spared the mid inferolateral wall (white arrow), pattern typical for Fabry disease. (c) Latest MRI shows interval development of mild diffuse patchy mid wall enhancement of left ventricle (arrow heads). (d) T1 value of left ventricular mid chamber shows with pseudonormalization of T1 value (1020 ms) without late gadolinium enhancement. (*Machine specific normal range of native T1 value: 1000 ms to 1050 ms.)

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IMAGING FEATURES LVH

LVH is the most common structural change reported in FD and cardiac MRI is the gold standard for the assessment of myocardial wall thickness and mass.[3] Some studies suggested that including the papillary muscle mass (due to papillary muscle hypertrophy) in the left ventricular mass, calculation can allow earlier detection of increased myocardial mass in FD.[7] Patients typically present with concentric LVH, which later becomes asymmetrical with markedly thickened septum compared to the inferolateral left ventricular wall, mimicking obstructive HCM [Figures 1a-d and 2a-c].[3] The inferolateral wall appears less thick because of underlying replacement fibrosis. Left ventricular outflow tract obstruction may be present both at rest [Figure 3a-b] and provoked by exercise.[1]

Figure 2: A 68-year-old female Fabry disease patient with left ventricular hypertrophy . (a) Short-axis cine of left ventricle mid chamber at end diastolic phase shows asymmetrical left ventricular hypertrophy relatively spared the mid chamber inferolateral wall (white arrowheads). (b) Delayed post gadolinium phase-sensitive inversion recovery T1 -weighted sequence shows patchy mid left ventricle most extensive at mid chamber inferolateral wall (white arrow). (c) Native T1 mapping at left ventricular mid chamber short-axis shows pseudonormalization of T1 values at inferolateral wall (1025ms) and decreased T1 values in rest of the left ventricular wall.

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Figure 3: A 64-year-old male Fabry disease patient with left ventricular hypertrophy. (a) The three chamber view cine at systolic phase shows hypertrophic left ventricular wall, left ventricular outflow tract obstruction with low signal jet at the outflow tract (white arrow) and systolic anterior motion of the mitral valve (white arrowhead). (b) The four chamber view cine at systole (white arrow) demonstrates mitral regurgitation during systole with a low signal jet above the mitral valve.

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Cardiac function and regional wall motion abnormalities

Cardiac MRI is highly accurate and reproducible in measuring ejection fraction and ventricular volume.[3] Left ventricular ejection fraction and diastolic function are usually preserved in the early stage of disease.[1] When posterolateral basal mid-myocardial fibrosis develops, wall thinning and hypokinesia or akinesia could be observed in the region.[1] Mild-to-moderate diastolic dysfunction and restrictive filling are only seen in very advanced stage.[1] Right ventricular hypertrophy is sometimes present but the ejection function is usually preserved [Figure 4].[1]

Figure 4: A 67-year-old male Fabry disease patient. Short axis mid chamber view at end diastole shows right ventricular hypertrophy predominantly at inferior and free lateral walls (white arrowheads), while ejection fraction is preserved.

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Valvular involvement

Structural valve abnormalities are frequently associated with LVH.[8] The aortic and mitral valves are most likely involved with valvular thickening and mild-to-moderate regurgitations [Figure 3a-b and 5a-b].[1] Aortic remodeling secondary to aortic valve disease could result in mild aortic ectasia or dilatation [Figure 5b]. Mild thickening of the aortic valve was reported in 25% of FD patients. Mitral valve prolapse and systolic restriction are seen in cases with extensive posterolateral fibrosis.[1]

Figure 5: A 62-year-old male Fabry disease patient with left ventricular hypertrophy and moderate aortic regurgitation. (a) The three chamber view cine at diastolic phase shows hypertrophic left ventricular wall. A low signal jet seen below the aortic valve (white arrow) during diastole represents regurgitation. (b) The coronal left ventricular outflow tract view shows ectasia of ascending thoracic aorta (measured 3.9cm in calibre on black double arrows) secondary to aortic valve disease.

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Late gadolinium enhancement (LGE)

LGE reflects replacement fibrosis due to chronic inflammation and it is present in almost half of FD patients. About 75% of cases would involve the basal and mid inferolateral wall of the left ventricle.[3] Progressive myocardial fibrosis usually starts in the mid-myocardial layer of the basal inferolateral LV wall, sparing the subendocardium [Figure 2a-c, and 6a-c].[1] This pattern is typical to FD and can help to distinguish it from other causes of symmetric LVH.[9] It has been hypothesized that physical stress is the most prominent at inferolateral wall of left ventricle, leading to subclinical myocarditis and subsequent tissue injury.[9] In advanced disease, LGE can be extensive with a less specific appearance [Figure 1a-d]. In such cases, T1 mapping can be helpful to differentiate it with other causes of LVH. On the other hand, about one-fourth of FD females can develop LGE without LVH.[3]

Figure 6: A 67-year-old male Fabry disease patient. (a, b and c) Delayed post gadolinium phase-sensitive inversion recovery T1-weighted sequences in three-chamber, four-chamber and short-axis views show patchy mid wall late gadolinium enhancement in the left ventricular wall predominantly involving the basal inferior and lateral walls (white arrows), which is characteristic of Fabry disease cardiomyopathy.

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T1 mapping

Accumulation of glycosphingolipids inside lysosomes in FD significantly shortens native T1 values.[3] Native T1 values are reduced in the early stage of FD but begin to normalize with progressive accumulation of glycosphingolipids (pseudonormalization) [Figures 1a-d and 2a-c].[3] T1 values can be increased in the advanced stage due to replacement fibrosis and ongoing inflammation (edema).[3] Previous study concluded that reduced native myocardial T1 values are the most sensitive and specific MRI parameter in FD patients.[3] Studies have also shown that it can reliably differentiate patients with FD from other pathogenesis with LVH.[10] Reduced native T1 values can be present in the absence of LVH and basal inferolateral wall LGE [Figure 7]. Therefore, it may identify patients with early cardiac involvement and provide appropriate treatments for those patients.

Figure 7: A 50-year-old male Fabry disease patient at storage phase of cardiomyopathy. Native T1 mapping at the mid left ventricular short-axis shows low T1 value (926ms). There is no left ventricular hypertrophy or late gadolinium enhancement in this patient.

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T2 mapping

Elevated native T2 values in the early stage of myocardial involvement are due to myocardial edema or inflammation.[3] In the later stage, native T2 values would elevate corresponding to areas of LGE in the basal inferolateral wall, indicating chronic inflammation [Figure 8a-c].[3] Chronic T2 elevation in LGE areas and elevation of global T2 values are both associated with poor outcomes.[3]

Figure 8: A 72-year-old male Fabry disease patient in later stage of cardiomyopathy. (a) Delayed post gadolinium phase-sensitive inversion recovery T1 -weighted sequence in mid chamber short-axis view show mid wall late gadolinium enhancement affecting mid inferolateral wall of left ventricle which is not thickened (white arrow). (b and c) Focally elevated T1 value (1118ms) and T2 value (60ms) at the mid chamber inferolateral wall with corresponding mid wall late gadolinium enhancement is suggestive of chronic inflammation. The remaining LV myocardium show diffusely decrease T1 value with normal T2 value.

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Common differential diagnosis

It is challenging to distinguish FD cardiomyopathy from other forms of unexplained LVH. Common differential includes HCM, hypertensive heart disease, aortic stenosis, and cardiac amyloidosis. They can be differentiated by looking at the LVH pattern, LGE pattern, native T1 mapping and T2 mapping on cardiac MRI which is summarized in Table 1.

Table 1: MR characteristics of Fabry disease and other etiologies of hypertrophic cardiomyopathy.

Etiology LVH pattern LGE pattern Native T1 mapping T2 mapping Fabry disease Concentric LV wall thickening, relatively spared inferolateral wall at late stage Inferolateral mid-wall LGE. Extensive LGE can occur at late stage Globally reduced, normal or elevated in advanced disease Elevated in chronic inflammation, typically in mid inferolateral wall HCM Most commonly asymmetrical septal involvement. Other variants include apical, midventricular, mass-like, symmetric, and non-contiguous HCM Patchy mid-wall LGE in the areas of hypertrophy Elevated Elevated in the areas of active tissue injury Hypertensive heart disease Concentric mild (<15 mm) LV wall thickening with asymmetric basal septal involvement Infrequent. Non-specific pattern or mid-wall LGE. Normal. Normal. Aortic stenosis Normal, concentric or eccentric LV wall thickening Combined mid-wall and junctional patterns commonly affecting the mid-basal septum and inferior wall Elevated secondary to myocardial fibrosis or severe disease Elevated in severe disease. Cardiac amyloidosis Concentric LV wall thickening Diffuse LV transmural or subendocardial LGE Elevated Elevated due to the toxic effect of amyloid deposition. CONCLUSION

Recognizing characteristic cardiac manifestations of FD on cardiac MRI is important to distinguish it from other forms of LVH and guide disease management.