Cardiac Involvement in Fabry Disease and the Role of Multimodality Imaging in Diagnosis and Disease Monitoring

Fabry disease (FD) is a rare X-chromosome linked lysosomal storage disorder caused by mutations in the GLA gene, leading to an absence or deficiency of the enzymatic activity of α-GAL.1 There are more than 1000 GLA gene variants identified so far and can be categorized as pathogenic mutations, variants of unknown significance (VUS, such as p.R112H, p.M296I, p.R118C), and benign polymorphisms (eg, p.D313Y, p.E66Q, p.E66Q, A143T). Benign polymorphisms and VUS have a higher frequency and can be seen during screening but may not be related to FD manifestations.2 The deficiency of α-GAL activity impairs the breakdown of the glycosphingolipid, GL3 - leading to the accumulation of GL3 and lyso-GL3 in cells throughout the body, including the blood vessels, heart, nervous system, skin, kidneys, gastrointestinal system, and the eyes.

The prevalence of FD in the general population is estimated to be about 1 in 40,000 to 1 in 117,000.1 Up to 4%-8% of nonobstructive hypertrophic cardiomyopathy (HCM) patients may have FD. Given that the prevalence of HCM is 1 in 300 in the adult population,3,4 FD may be more prevalent than previously believed. Classic FD is characterized by absent or very low α-GAL activity,5 early-onset, male predominance, and progressive multisystemic involvement. Atypical FD on the other hand has some residual or lower than normal α-GAL activity,5 variable onset, and predominantly cardiac involvement. Heterozygous females may have low-normal or variably deficient α-GAL activity, variable onset, and may develop significant multisystemic manifestations6,7 depending on the underlying GLA mutation (Table 1). X-chromosome inactivation may partly account for the lesser severity and later age of presentation in females1 - it may be delayed by 10-15 years compared to males. Women are also more likely to have isolated cardiac disease and can develop myocardial fibrosis and diastolic dysfunction without myocardial hypertrophy.8

Misdiagnoses are common in FD, with a longer period of diagnostic delay in females compared to males7,9 (Fig 1A). FD can significantly reduce life expectancy, approximately by 20 years in males and 15 years in females10,11 (Fig 1B). Cardiac disease is the major cause of death in FD, with a 3-fold increase in cardiac events compared to the general population.

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